Piperidine derivatives having ccr3 antagonism

ABSTRACT

The invention provides low molecular compounds having activity which inhibits binding of CCR3 ligands to CCR3 on target cells, i.e. CCR3 antagonists. The invention also provides compounds represented by formula (I) below, pharmaceutically acceptable acid adducts thereof, or pharmaceutically acceptable C 1 -C 6  alkyl adducts thereof, as well as pharmaceutical compositions comprising them as effective ingredients, which are useful for treatment or prevention of diseases associated with CCR3, such as asthma and allergic rhinitis.

TECHNICAL FIELD

The present invention relates to piperidine derivatives with CCR3 (C—CChemokine Receptor 3) antagonism. More specifically, the inventionrelates to CCR3 antagonists with anticipated effects as therapeuticand/or prophylactic agents for allergic conditions such as bronchialasthma, allergic rhinitis, atopic dermatitis, urticaria, contactdermatitis or allergic conjunctivitis, inflammatory bowel diseases suchas ulcerative colitis or Crohn's disease, diseases whose major factor isaccelerated or sustained increase or tissue infiltration of eosinophils,basophils or activated T cells, such as eosinophilia, eosinophilicgastroenteritis, eosinophilic enteropathy, eosinophilic fasciitis,eosinophilic granuloma, eosinophilic pustular folliculitis, eosinophilicpneumonia or eosinophilic leukemia, or AIDS (Acquired Immune DeficiencySyndrome) caused by infection with HIV (Human Immunodeficiency Virus).

BACKGROUND ART

In recent years, the concept that allergic conditions such as bronchialasthma are fundamentally diseases of chronic inflammation has beenestablished, and accumulation of eosinophils at local sites ofinflammation is considered to be a major feature thereof (for example,see Busse, W. W. J. Allergy Clin. Immunol. 1998, 102, S17-S22; Fujisawa,T. Gendai Iryou 1999, 31, 1297). For example, administration ofanti-adhesion molecule (ICAM-1) antibodies in monkey asthma modelsinhibits accumulation of eosinophils and suppresses late asthmaticsymptoms, suggesting the importance of eosinophils in allergicconditions (Wegner, C. D. et al. Science, 1990, 247, 456).

Eotaxins have been identified as specific chemotactic factors inducingaccumulation and/or migration of eosinophils (eosinophil-specificchemokines) (for example, see Jose, P. J., et al. J. Exp. Med. 1994,179, 881; Garcia-Zepda, E. A. et al. Nature Med. 1996, 2, 449; Ponath,P. D. et al. J. Clin. Invest. 1996, 97, 604; Kitaura, M. et al. J. Biol.Chem. 1996, 271, 7725). It has also been demonstrated that eotaxins bindto CCR3 expressed on eosinophils, exhibiting an effect of promotingaccumulation and/or migration of eosinophils. In addition, chemotacticfactors such as eotaxin-2, RANTES (abbreviation for Regulated onActivation, Normal T-cell Expressed and Secreted) antibodies, MCP-2(abbreviation for Monocyte Chemoattractant Protein-2), MCP-3(abbreviation for Monocyte Chemoattractant Protein-3), MCP-4(abbreviation for Monocyte Chemoattractant Protein-4) and the like arealso known to exhibit effects similar to those of eotaxins via CCR3,although their potency is weaker than that of eotaxins (for example, seeKitaura, M. et al. J. Biol. Chem. 1996, 271, 7725; Daugherty, B. L. etal. J. Exp. Med. 1996, 183, 2349; Ponath, P. D. et al. J. Exp. Med.1996, 183, 2437; Hiath, H. et al. J. Clin. Invest. 1997, 99, 178; Patel,V. P. et al. J. Exp. Med. 1997, 185, 1163; Forssmann, U. et al. J. Exp.Med. 185, 2171, 1997).

The reported effects of eotaxins on eosinophils include not onlyinducing migration of eosinophils, but also effects related toeosinophil activation, such as augmenting expression of adhesionmolecule receptor (CD11b) (for example, see Tenscher, K. et al. Blood,1996, 88, 3195), accelerating production of active oxygen (for example,see Elsner, J. et al. Eur. J. Immunol. 1996, 26, 1919), and promotingrelease of EDN (Eosinophil-Derived Neurotoxin) (see El-Shazly, et al.Int. Arch. Allergy Immunol. 1998, 117 (suppl. 1), 55). Eotaxins havealso been reported to accelerate liberation of eosinophils and theirprecursors from the bone marrow into the blood (for example, seePalframan, R. T. et al. Blood 1998, 91, 2240).

Numerous reports indicate that eotaxins and CCR3 play important roles inallergic conditions such as bronchial asthma. For example, it has beenreported that infiltration of eosinophils is suppressed by anti-eotaxinantibodies in mouse asthma models (Gonzalo, J.-A. et al. J. Clin.Invest. 1996, 98, 2332), that infiltration of eosinophils is suppressedby anti-eotaxin antiserum in mouse cutaneous allergy models (Teixeira,M. M. et al. J. Clin. Invest. 1997, 100, 1657), that formation ofpulmonary granulomas is suppressed by anti-eotaxin antibodies in mousemodels (see Ruth, J. H. et al. J. Immunol. 1998, 161, 4276), thatinfiltration of eosinophils is suppressed in eotaxin gene-deficientmouse asthma models and interstitial keratitis models (see Rothenberg,M. E. et al. J. Exp. Med. 1997, 185, 785), that expression of eotaxinsand CCR3 is augmented on both the genetic and protein level in asthmaticbronchi compared to healthy controls (see Ying, S. et al. Eur. J.Immunol. 1997, 27, 3507), and that eotaxin expression is augmented innasal subepithelial tissue of chronic sinusitis patients (Am. J. Respir.Cell Mol. Biol. 1997, 17, 683).

Also, based on reports that eotaxins are abundantly expressed at sitesof inflammation in the inflammatory bowel diseases of ulcerative colitisand Crohn's disease (see Garcia-Zepda, E. A. et al. Nature Med. 1996, 2,449), it is believed that eotaxins also play an important role in suchinflammatory bowel diseases.

These data strongly suggest that eotaxins, via CCR3-mediatedaccumulation and activation of eosinophils at lesion sites, areintimately involved in the onset, progression or sustaining of diseaseswherein eosinophils are closely associated with developing lesions,including, for example, allergic conditions such as bronchial asthma,allergic rhinitis, atopic dermatitis, urticaria, contact dermatitis orallergic conjunctivitis, inflammatory bowel diseases such as ulcerativecolitis or Crohn's disease, and eosinophilia, eosinophilicgastroenteritis, eosinophilic enteropathy, eosinophilic fasciitis,eosinophilic granuloma, eosinophilic pustular folliculitis, eosinophilicpneumonia or eosinophilic leukemia. In addition, since CCR3 is expressednot only on eosinophils but also on basophils and Th2 lymphocytes, andeotaxins induce intracellular calcium ion concentration increase andmigration of these cells, it is believed that eotaxins and CCR3 areinvolved in the onset, progression and sustaining of diseases associatedwith these cells, such as allergic conditions, also via accumulation andactivation of basophils and Th2 lymphocytes (for example, see Sallusto,F. et al. Science 1997, 277, 2005; Gerber, B. O. et al. Current Biol.1997, 7, 836; Sallusto, F. et al. J. Exp. Med. 1998, 187, 875;Uguccioni, M. et al. J. Clin. Invest. 1997, 100, 1137; Yamada, H. et al.Biochem Biophys. Res. Commun. 1997, 231, 365).

Consequently, compounds which inhibit binding of CCR3 to CCR3 ligandssuch as eotaxins, or in other words CCR3 antagonists, should inhibit theeffects of the CCR3 ligands on target cells and are therefore expectedbe useful as therapeutic and/or prophylactic agents for allergicconditions and inflammatory bowel disease. Yet, no agents having suchactivity have been known.

Moreover, it has also been reported that HIV-1 (Human ImmunodeficiencyVirus-1) may utilize CCR3 to infect host cells, and therefore CCR3antagonists are also expected to be useful as therapeutic orprophylactic agents for AIDS (Acquired Immune Deficiency Syndrome)caused by HIV infection (for example, see Choe, H. et al. Cell 1996, 85,1135; Doranz, B. J. et al. Cell 1996, 85, 1149).

Recently, piperidine derivatives (see Patent Specification No.WO9802151, Patent Specification No. WO9804554, Patent Specification No.WO0029377, Patent Specification No. WO0031033, Patent Specification No.WO0035449, Patent Specification No. WO0035451, Patent Specification No.WO0035452, Patent Specification No. WO0035453, Patent Specification No.WO0035454, Patent Specification No. WO0035876, Patent Specification No.WO0035877, Patent Specification No. WO0051607, Patent Specification No.WO0051608, Patent Specification No. WO0051609, Patent Specification No.WO0051610, Patent Specification No. WO0053600, Patent Specification No.WO0058305, Patent Specification No. WO0059497, Patent Specification No.WO0059498, Patent Specification No. WO0059502, Patent Specification No.WO0059503, Patent Specification No. WO0076511, Patent Specification No.WO0076512, Patent Specification No. WO0076513, Patent Specification No.WO0076514, Patent Specification No. WO0076972, Patent Specification No.WO0076973, Patent Specification No. WO0105782, Patent Specification No.WO0114333, Patent Specification No. WO0164216, Patent Specification No.WO0177101, Patent Specification No. WO0192227, Patent Specification No.WO0198268, Patent Specification No. WO0198269, Patent Specification No.WO0198270, Patent Specification No. WO0202525, Patent Specification No.WO0204420), piperazine derivatives (see Patent Specification No.EP0903349, Patent Specification No. WO0034278, Patent Specification No.WO0102381) and other low molecular compounds (see Patent SpecificationNo. WO9955324, Patent Specification No. WO9955330, Patent SpecificationNo. WO0004003, Patent Specification No. WO0027800, Patent SpecificationNo. WO0027835, Patent Specification No. WO0027843, Patent SpecificationNo. WO0031032, Patent Specification No. WO0041685, Patent SpecificationNo. WO0053172, Patent Specification No. WO0109088, Patent SpecificationNo. WO0128987, Patent Specification No. WO0129000), have been reportedto exhibit antagonism against CCR3. However, these compounds differ fromthe compounds of the invention.

Patent Specification No. WO0107436 and Patent Specification No.WO9937304 describe oxopiperazine derivatives having inhibiting activityon Factor Xa, but they do not specifically mention the piperidinederivatives of the invention, nor is it known whether theseoxopiperazine derivatives exhibit competitive inhibition for CCR3.Patent Specification No. WO0132615 and Patent Specification No.WO02684.09 describe N-substituted piperidine derivatives havingNMDA/NR2B antagonism, but they do not specifically mention thepiperidine derivatives of the invention, nor is it known whether theseN-substituted piperidine derivatives exhibit competitive inhibition forCCR3.

It is an object of the present invention to provide low molecularcompounds having activity which inhibits binding of CCR3 ligands to CCR3on target cells, i.e. CCR3 antagonists.

It is another object of the invention to provide therapeutic and/orprophylactic agents for diseases of which a causal factor is binding ofa CCR3 ligand to CCR3 on target cells.

DISCLOSURE OF THE INVENTION

The present invention provides the following:

(1) Compounds represented by the following formula (I):

[wherein R¹ represents phenyl, C₃-C₈ cycloalkyl or an aromaticheterocyclic group (having 1-3 atoms selected from the group consistingof oxygen, sulfur and nitrogen as hetero atoms),the phenyl or aromatic heterocyclic group of R¹ may optionally fuse witha benzene ring or aromatic heterocyclic group (having 1-3 atoms selectedfrom the group consisting of oxygen, sulfur and nitrogen as heteroatoms) to form a fused ring,the phenyl, C₃-C₈ cycloalkyl or aromatic heterocyclic group, or fusedring, in R¹ may be unsubstituted, or substituted with one or moresubstituents selected from the group consisting of halogens, hydroxy,cyano, nitro, carboxyl, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₂-C₆ alkenyl,C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₃-C₅ alkylene, C₂-C₄ alkyleneoxy, C₁-C₃alkylenedioxy, phenyl, phenoxy, phenylthio, benzyl, benzyloxy,benzoylamino, formyl, C₂-C₇ alkanoyl, C₂-C₇ alkoxycarbonyl, C₂-C₇alkanoyloxy, C₂-C₇ alkanoylamino, C₁-C₆ alkylsulfonyl, C₃-C₈(alkoxycarbonyl)methyl, amino, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, carbamoyl, C₂-C₇ N-alkylcarbamoyl, C₄-C₉N-cycloalkylcarbamoyl, N-phenylcarbamoyl, piperidylcarbonyl,morpholinylcarbonyl, pyrrolidinylcarbonyl, piperazinylcarbonyl,N-methoxycarbamoyl, (formyl)amino and ureido, and the substituent of thephenyl, C₃-C₈ cycloalkyl or aromatic heterocyclic group, or fused ring,of R¹ may be unsubstituted, or substituted with one or more substituentsselected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, phenyl, C₃-C₅ alkylene, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl,C₁-C₆ alkoxy, C₁-C₆ alkylthio, amino, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, pyrrolidinyl, piperidyl, C₃-C₇ lactam, carbamoyl, C₂-C₇N-alkylcarbamoyl, C₂-C₇ alkoxycarbonyl, carboxyl, hydroxy, benzoyl,cyano, trifluoromethyl, halogen and tert-butoxycarbonylamino,provided that when R¹ is C₃-C₈ cycloalkyl, the substituent does notinclude amino, mono(C₁-C₆ alkyl)amino or di(C₁-C₆ alkyl)amino;

p represents an integer of 1-6;

R² and R³ may be the same or different and each independently representshydrogen, C₁-C₆ alkyl or phenyl, where the C₁-C₆ alkyl or phenyl groupof R² and R³ may be unsubstituted, or substituted with one or moresubstituents selected from the group consisting of halogens, hydroxy,C₁-C₆ alkyl, C₂-C₇ alkoxycarbohyl, amino, carbamoyl, carboxyl, cyano andC₁-C₆ alkoxy;

X represents —CO—, —SO₂—, —CH₂—, —CS— or a single bond;

q represents 0 or 1;

r represents 0 or 1;

Y represents —(R⁴)C═C(R⁵)—, —S— or —NR⁸—;

R⁴, R⁵, R⁶ and R⁷ may be the same or different, and each independentlyrepresents hydrogen, a halogen, hydroxy, cyano, nitro, carboxyl, C₁-C₆alkyl, C₃-C₈ cycloalkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio,C₃-C₅ alkylene, C₂-C₄ alkyleneoxy, C₁-C₃ alkylenedioxy, phenyl, phenoxy,phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzoylamino, formyl,C₂-C₇ alkanoyl, C₂-C₇ alkoxycarbonyl, C₂-C₇ alkanoyloxy, C₂-C₇alkanoylamino, C₄-C₁₀ cycloalkanoylamino, C₃-C₇ alkenoylamino, C₁-C₆alkylsulfonyl, C₁-C₆ alkylsulfonylamino, C₃-C₈ (alkoxycarbonyl)methyl,amino, mono(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, carbamoyl, C₂-C₇N-alkylcarbamoyl, C₄-C₉ N-cycloalkylcarbamoyl, N-phenylcarbamoyl,N—(C₇-C₁₂ phenylalkyl)carbamoyl, piperidylcarbonyl, morpholinylcarbonyl,pyrrolidinylcarbonyl, piperazinylcarbonyl, N-methoxycarbamoyl,sulfamoyl, C₁-C₆ N-alkylsulfamoyl, (formyl)amino, (thioformyl)amino,ureido or thioureido, where the aforementioned groups of R⁴, R⁵, R⁶ andR⁷ each may be independently unsubstituted, or substituted with one ormore substituents selected from the group consisting of C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, phenyl, C₃-C₅ alkylene, C₃-C₈ cycloalkyl,C₃-C₈ cycloalkenyl, C₁-C₆ alkoxy, (C₁-C₆ alkoxy) (C₁-C₆ alkoxy),phenyl(C₁-C₆ alkoxy), C₁-C₆ alkylthio, amino, mono(C₁-C₆ alkyl)amino,di(C₁-C₆ alkyl)amino, pyrrolidinyl, piperidyl, (C₂-C₇alkanoyl)piperidyl, C₃-C₇ lactam, carbamoyl, C₂-C₇ N-alkylcarbamoyl,C₄-C₉ N-cycloalkylcarbamoyl, N-phenylcarbamoyl, N—(C₇-C₁₂phenylalkyl)carbamoyl, C₂-C₇ alkanoylamino, C₂-C₇ alkoxycarbonyl,carboxyl, hydroxy, benzoyl, cyano, trifluoromethyl, halogens,tert-butoxycarbonylamino, C₁-C₆ alkylsulfonyl and heterocycles oraromatic heterocycles (where a heterocycle or aromatic heterocycle has1-3 atoms selected from the group consisting of oxygen, sulfur andnitrogen as hetero atoms, and may be substituted with C₁-C₆ alkyl); and

R⁸ represents hydrogen or C₁-C₆ alkyl, where the C₁-C₆ alkyl group of R⁸may be unsubstituted, or substituted with one or more substituentsselected from the group consisting of halogens, hydroxy, cyano, nitro,carboxyl, carbamoyl, mercapto, guanidino, C₃-C₈ cycloalkyl, C₁-C₆alkoxy, C₁-C₆ alkylthio, phenyl (where phenyl may be substituted, orsubstituted with one or more substituents selected from the groupconsisting of halogens, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy andbenzyloxy), phenoxy, benzyloxy, benzyloxycarbonyl, C₂-C₇ alkanoyl, C₂-C₇alkoxycarbonyl, C₂-C₁₇ alkanoyloxy, C₂-C₇ alkanoylamino, C₂-C₇N-alkylcarbamoyl, C₂-C₆ alkylsulfonyl, amino, mono(C₁-C₆ alkyl)amino,di(C₁-C₆ alkyl)amino and ureido],

pharmaceutically acceptable acid adducts thereof, or pharmaceuticallyacceptable C₁-C₆ alkyl adducts thereof;

(2) Compounds according to (1), pharmaceutically acceptable acid adductsthereof, or pharmaceutically acceptable C₁-C₆ alkyl adducts thereof,wherein X in formula (I) is —SO₂—;

(3) Compounds according to (1), pharmaceutically acceptable acid adductsthereof, or pharmaceutically acceptable C₁-C₆ alkyl adducts thereof,wherein X in formula (I) is —CO—;

(4) Compounds according to (1), pharmaceutically acceptable acid adductsthereof, or pharmaceutically acceptable C₁-C₆ alkyl adducts thereof,wherein X in formula (I) is —CH₂—;

(5) Compounds according to (1), pharmaceutically acceptable acid adductsthereof, or pharmaceutically acceptable C₁-C₆ alkyl adducts thereof,wherein X in formula (I) is —CS—;

(6) Compounds according to (1), pharmaceutically acceptable acid adductsthereof, or pharmaceutically acceptable C₁-C₆ alkyl adducts thereof,wherein X in formula (I) is a single bond;

(7) Compounds according to any one of (1) to (6), pharmaceuticallyacceptable acid adducts thereof, or pharmaceutically acceptable C₁-C₆alkyl adducts thereof, wherein Y in formula (I) is —(R⁴)C═C(R⁵)—;

(8) Compounds according to any one of (1) to (6), pharmaceuticallyacceptable acid adducts thereof, or pharmaceutically acceptable C₁-C₆alkyl adducts thereof, wherein Y in formula (I) is —S—;

(9) Compounds according to any one of (1) to (6), pharmaceuticallyacceptable acid adducts thereof, or pharmaceutically acceptable C₁-C₆alkyl adducts thereof, wherein Y in formula (I) is —NR⁸—;

(10) Compounds according to any one of (1) to (9), pharmaceuticallyacceptable acid adducts thereof, or pharmaceutically acceptable C₁-C₆alkyl adducts thereof, wherein R¹ in formula (I) is substituted orunsubstituted phenyl;

(11) Compounds according to any one of (1) to (10), pharmaceuticallyacceptable acid adducts thereof, or pharmaceutically acceptable C₁-C₆alkyl adducts thereof, wherein R² in formula (I) is hydrogen;

(12) Compounds according to any one of (1) to (11), pharmaceuticallyacceptable acid adducts thereof, or pharmaceutically acceptable C₁-C₆alkyl adducts thereof, wherein R³ in formula (I) is hydrogen;

(13) Compounds according to any one of (1) to (12), pharmaceuticallyacceptable acid adducts thereof, or pharmaceutically acceptable C₁-C₆alkyl adducts thereof, wherein q=0 and r=0 in formula (I);

(14) Compounds according to any one of (1) to (12), pharmaceuticallyacceptable acid adducts thereof, or pharmaceutically acceptable C₁-C₆alkyl adducts thereof, wherein q=1 and r=0 in formula (I);

(15) Compounds according to any one of (1) to (12), pharmaceuticallyacceptable acid adducts thereof, or pharmaceutically acceptable C₁-C₆alkyl adducts thereof, wherein q=0 and r=1 in formula (I);

(16) Compounds according to any one of (1) to (15), pharmaceuticallyacceptable acid adducts thereof, or pharmaceutically acceptable C₁-C₆alkyl adducts thereof, wherein p=1 in formula (I);

(17) Compounds according to (2), pharmaceutically acceptable acidadducts thereof, or pharmaceutically acceptable C₁-C₆ alkyl adductsthereof, wherein Y is (R⁴)C═C(R⁵)—, R¹ is substituted or unsubstitutedphenyl, R² is hydrogen, R³ is hydrogen, q=0, r=0 and p=1 in formula (I);

(18) Compounds according to (3), pharmaceutically acceptable acidadducts thereof, or pharmaceutically acceptable C₁-C₆ alkyl adductsthereof, wherein Y is —(R⁴)C═C(R⁵)—, R¹ is substituted or unsubstitutedphenyl, R² is hydrogen, R³ is hydrogen, q=0, r=0 and p=1 in formula (I);

(19) Compounds according to (4), pharmaceutically acceptable acidadducts thereof, or pharmaceutically acceptable C₁-C₆ alkyl adductsthereof, wherein Y is —(R⁴)C═C(R⁵)—, R¹ is substituted or unsubstitutedphenyl, R² is hydrogen, R³ is hydrogen, q=0, r=0 and p=1 in formula (I);

(20) Compounds according to (6), pharmaceutically acceptable acidadducts thereof, or pharmaceutically acceptable C₁-C₆ alkyl adductsthereof, wherein Y is —(R⁴)C═C(R⁵)—, R¹ is substituted or unsubstitutedphenyl, R² is hydrogen, R³ is hydrogen, q=0, r=0 and p=1 in formula (I);

(21) Compounds according to any one of (17) to (20), pharmaceuticallyacceptable acid adducts thereof or pharmaceutically acceptable C₁-C₆alkyl adducts thereof, wherein R⁴ and R⁵ in formula (I) may be the sameor different and each is independently hydrogen, a halogen, hydroxy,cyano, nitro, carboxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₇ alkoxycarbonyl,C₂-C₇ alkanoylamino, C₁-C₆ alkylsulfonyl, amino, carbamoyl, C₂-C₇N-alkylcarbamoyl, sulfamoyl or C₁-C₆ N-alkylsulfamoyl;

(22) Compounds according to any one of (17) to (20), pharmaceuticallyacceptable acid adducts thereof or pharmaceutically acceptable C₁-C₆alkyl adducts thereof, wherein R⁴ and R⁵ in formula (I) may be the sameor different and each is independently a halogen, hydroxy, cyano, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₇ alkoxycarbonyl, C₁-C₆ alkylsulfonyl orC₁-C₆ N-alkylsulfamoyl;

(23) Compounds according to any one of (17) to (22), pharmaceuticallyacceptable acid adducts thereof or pharmaceutically acceptable C₁-C₆alkyl adducts thereof, wherein each R¹ in formula (I) above may be thesame or different and is independently hydrogen, a halogen, hydroxy,cyano, nitro, C₁-C₆ alkyl or C₁-C₆ alkoxy;

(24) Pharmaceutical compositions with CCR3 antagonism which comprise aseffective ingredients thereof compounds represented by formula (I)according to any one of (1) to (23), pharmaceutically acceptable acidadducts thereof or pharmaceutically acceptable C₁-C₆ alkyl adductsthereof;

(25) Prophylactic and/or therapeutic compositions for any diseaseassociated with CCR3, which comprise as effective ingredients thereofcompounds represented by formula (I) according to any one of (1) to(23), pharmaceutically acceptable acid adducts thereof or apharmaceutically acceptable C₁-C₆ alkyl adducts thereof;

(26) Prophylactic and/or therapeutic compositions according to (25),wherein the disease is an allergic condition;

(27) Prophylactic and/or therapeutic compositions according to (26),wherein the allergic condition is bronchial asthma, allergic rhinitis,atopic dermatitis, urticaria, contact dermatitis or allergicconjunctivitis;

(28) Prophylactic and/or therapeutic compositions according to (25),wherein the disease is an inflammatory bowel disease;

(29) Prophylactic and/or therapeutic compositions according to (25),wherein the disease is AIDS (Acquired Immune Deficiency Syndrome);

(30) Prophylactic and/or therapeutic compositions according to (25),wherein the disease is eosinophilia, eosinophilic gastroenteritis,eosinophilic enteropathy, eosinophilic fasciitis, eosinophilicgranuloma, eosinophilic pustular folliculitis, eosinophilic pneumonia oreosinophilic leukemia.

BEST MODE FOR CARRYING OUT THE INVENTION

The number of substituents on the phenyl, C₃-C₈ cycloalkyl or aromaticheterocyclic group, or fused ring, of R¹, and the number of substituentson the substituents of the phenyl, C₃-C₈ cycloalkyl or aromaticheterocyclic group, or fused ring, of R¹ may be any chemically possiblenumber, but it is preferably 0-15, more preferably 0-10 and morepreferably 0-7.

The term “C₃-C₈ cycloalkyl” for R¹ means a cyclic alkyl group such as,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl, and as preferred examples there may bementioned cyclopropyl, cyclopentyl and cyclohexyl.

The term “aromatic heterocyclic group (having 1-3 atoms selected fromthe group consisting of oxygen, sulfur and nitrogen as hetero atoms)”for R¹ means an aromatic heterocyclic group such as, for example,thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isooxazolyl,thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazinyl, triazolyl,oxadiazolyl(furazanyl) or thiadiazolyl, and as preferred examples theremay be mentioned thienyl, furyl, pyrrolyl and pyridyl.

The term “fused ring” for R¹ means a bicyclic aromatic heterocyclicgroup formed by fusing the phenyl or aromatic heterocyclic group with abenzene ring or an aromatic heterocyclic group (having 1-3 atomsselected from the group consisting of oxygen, sulfur and nitrogen ashetero atoms) at any possible position, and as preferred examples theremay be mentioned naphthyl, indolyl, benzofuranyl, benzothienyl, quinolyland benzoimidazolyl.

R¹ according to the invention is most preferably phenyl, thienyl,furanyl, pyrrolyl, naphthyl, benzothienyl, benzofuranyl or indolyl.

The term “halogen” as a substituent on the phenyl, C₃-C₈ cycloalkyl oraromatic heterocyclic group, or fused ring, of R¹ means fluorine,chlorine, bromine and iodine or the like, and as preferred examplesthere may be mentioned fluorine, chlorine, bromine or iodine.

The term “C₁-C₆ alkyl” as a substituent on R¹ means a C₁-C₆straight-chain or branched alkyl group such as, for example, methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl,tert-pentyl, isohexyl, 2-methylpentyl or 1-ethylbutyl, and as preferredexamples there may be mentioned methyl, ethyl, propyl and isopropyl.

The term “C₃-C₈ cycloalkyl” as a substituent on R¹ has the same meaningas “C₃-C₈ cycloalkyl” for R¹ itself, and the same preferred examples maybe mentioned.

The term “C₂-C₆ alkenyl” as a substituent on R¹ means a C₂-C₆straight-chain or branched alkenyl group such as, for example, vinyl,allyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl,4-pentenyl, 5-hexenyl or 4-methyl-3-pentenyl, and as preferred examplesthere may be mentioned vinyl and 2-methyl-1-propenyl.

The term “C₁-C₆ alkoxy” as a substituent on R¹ means a group comprisinga C₁-C₆ alkyl group and an oxy group, and as preferred examples theremay be mentioned methoxy and ethoxy.

The term “C₁-C₆ alkylthio” as a substituent on R¹ means a groupcomprising a C₁-C₆ alkyl group and a thio group, and as preferredexamples there may be mentioned methylthio and ethylthio.

The term “C₃-C₅ alkylene” as a substituent on R¹ means a C₃-C₅ divalentalkylene group such as, for example, trimethylene, tetramethylene,pentamethylene or 1-methyltrimethylene, and as preferred examples theremay be mentioned trimethylene and tetramethylene.

The term “C₂-C₄ alkyleneoxy” as a substituent on R¹ means a groupcomprising a C₂-C₄ divalent alkylene group and an oxy group, such as,for example, ethyleneoxy(—CH₂CH₂O—), trimethyleneoxy(—CH₂CH₂CH₂O—),tetramethyleneoxy (—CH₂CH₂CH₂CH₂O—) or1,1-dimethylethyleneoxy(—CH₂C(CH₃)₂O—), and as preferred examples theremay be mentioned ethyleneoxy and trimethyleneoxy.

The term “C₁-C₃ alkylenedioxy” as a substituent on R¹ means a groupcomprising a C₁-C₃ divalent alkylene group and two oxy groups, such as,for example, methylenedioxy(—OCH₂O—), ethylenedioxy(—OCH₂CH₂O—),trimethylenedioxy(—OCH₂CH₂CH₂O—) or propylenedioxy(—OCH₂CH(CH₃)O—), andas preferred examples there may be mentioned methylenedioxy andethylenedioxy.

The term “C₂-C₇ alkanoyl” as a substituent on R¹ means a C₂-C₇straight-chain or branched alkanoyl group such as, for example, acetyl,propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, isobutyryl,3-methylbutanoyl, 2-methylbutanoyl, pivaloyl, 4-methylpentanoyl,3,3-dimethylbutanoyl or 5-methylhexanoyl, and as a preferred examplethere may be mentioned acetyl.

The term “C₂-C₇ alkoxycarbonyl” as a substituent on R¹ means a groupcomprising the aforementioned C₁-C₆ alkoxy group and a carbonyl group,and as preferred examples there may be mentioned methoxycarbonyl andethoxycarbonyl.

The term “C₂-C₇ alkanoyloxy” as a substituent on R¹ means a groupcomprising the aforementioned C₂-C₇ alkanoyl and an oxy group, and as apreferred example there may be mentioned acetyloxy.

The term “C₂-C₇ alkanoylamino” as a substituent on R¹ means a groupcomprising the aforementioned C₂-C₇ alkanoyl group and an amino group,and as a preferred example there may be mentioned acetylamino.

The term “C₁-C₆ alkylsulfonyl” as a substituent on R¹ means a groupcomprising the aforementioned C₁-C₆ alkyl group and a sulfonyl group,and as a preferred example there may be mentioned methylsulfonyl.

The term “C₃-C₈ (alkoxycarbonyl)methyl” as a substituent on R¹ means agroup comprising the aforementioned C₂-C₇ alkoxycarbonyl group and amethyl group, and as preferred examples there may be mentioned(methoxycarbonyl)methyl and (ethoxycarbonyl)methyl.

The term “mono(C₁-C₆ alkyl)amino as a substituent on R¹ means an aminogroup substituted with the aforementioned C₁-C₆ alkyl group, and aspreferred examples there may be mentioned methylamino and ethylamino.

The term “di(C₁-C₆ alkyl)amino” as a substituent on R¹ means an aminogroup substituted with two identical or different C₁-C₆ alkyl groups,and as preferred examples there may be mentioned dimethylamino,diethylamino and N-ethyl-N-methylamino.

The term “C₂-C₇ N-alkylcarbamoyl” as a substituent on R¹ means a groupcomprising the aforementioned C₁-C₆ alkyl group and a carbamoyl group,and as preferred examples there may be mentioned N-methylcarbamoyl andN-ethylcarbamoyl.

The term “C₄-C₉ N-cycloalkylcarbamoyl” as a substituent on R¹ means agroup comprising the aforementioned C₃-C₈ cycloalkyl group and acarbamoyl group, and as preferred examples there may be mentionedN-cyclopentylcarbamoyl and N-cyclohexylcarbamoyl.

The term “piperidylcarbonyl” as a substituent on R¹ means a groupresulting from bonding a piperidine group and a carbonyl group, and as apreferred example there may be mentioned (1-piperidyl)carbonyl.

The term “morpholinylcarbonyl” as a substituent on R¹ means a groupresulting from bonding a morpholine group and a carbonyl group, and as apreferred example there may be mentioned (1-morpholinyl)carbonyl.

The term “pyrrolidinylcarbonyl” as a substituent on R¹ means a groupresulting from bonding a pyrrolidine group and a carbonyl group, and asa preferred example there may be mentioned (1-pyrrolidinyl)carbonyl.

The term “piperazinylcarbonyl” as a substituent on R¹ means a groupresulting from bonding a piperazine group and a carbonyl group, and as apreferred example there may be mentioned (1-piperazinyl)carbonyl.

As particularly preferred substituents on R¹ there may be mentionedhalogens, hydroxy, cyano, nitro, C₁-C₆ alkyl and C₁-C₆ alkoxy.

The term “C₂-C₆ alkynyl” as a substituent further substituting thesubstituent on the phenyl, C₃-C₈ cycloalkyl or aromatic heterocyclicgroup, or fused ring, of R¹, means a C₂-C₆ alkynyl group such as, forexample, ethynyl, methylethynyl and ethylethynyl, and as a preferredexample there may be mentioned ethynyl.

The term “C₃-C₈ cycloalkenyl” as a substituent further substituting thesubstituent on R¹ means a C₃-C₈ cyclic alkenyl group such as, forexample, cyclopentenyl, cyclohexenyl or 1,3-cyclohexadienyl, and as apreferred example there may be mentioned cyclohexenyl.

The term “C₃-C₇ lactam” as a substituent further substituting thesubstituent on R¹ means a group derived by removing one hydrogen from acyclic amide group such as, for example, 3-propanelactam,4-butanelactam, 5-pentanelactam or 6-hexanelactam, and as a preferredexample there may be mentioned “a group derived by removing one hydrogenfrom 4-butanelactam”.

The C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₃-C₅alkylene, C₃-C₈ cycloalkyl, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, C₂-C₇ alkoxycarbonyl or C₂-C₇ N-alkylcarbamoyl groups assubstituents further substituting the substituent on R¹ have the samedefinitions as the substituents on R¹, and the same preferred examplesmay be mentioned.

In formula (I), p represents an integer of 1-6, and preferably 1 or 3.

The number of substituents on the C₁-C₆ alkyl or phenyl group of R² andR³ according to the invention may be any chemically possible number, butit is preferably 0-13, more preferably 0-10 and more preferably 0-7.

The C₁-C₆ alkyl group of R² and R³ has the same definition as thesubstituent on R¹, and the same preferred examples may be mentioned.

The halogen, C₁-C₆ alkyl, C₂-C₇ alkoxycarbonyl and C₁-C₆ alkoxy groupsas substituents on the C₁-C₆ alkyl or phenyl group of R² and R³ have thesame definitions as the substituents on R¹, and the same preferredexamples may be mentioned.

Either R² and R³ of formula (I) preferably represents hydrogen, and mostpreferably both represent hydrogen.

In formula (I), X represents —CO—, —SO₂—, —CH₂—, —CS— or a single bond,all of which may be mentioned as preferred examples. Here, —CO—represents carbonyl, —SO₂-represents sulfonyl and —CS— representsthiocarbonyl.

In formula (I), q represents 0 or 1, and r represents 0 or 1. The caseswhere q=0 and r=0, q=1 and r=0, and q=0 and r=1 may be mentioned aspreferred examples.

In formula (I), Y represents —(R⁴)C═C(R⁵)—, —S— or —NR⁸—, all of whichmay be mentioned as preferred examples.

The number of substituents on the groups for R⁴, R⁵, R⁶ and R⁷ accordingto the invention may be any chemically possible number, but it ispreferably 0-15, more preferably 0-10 and more preferably 0-7.

The C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₃-C₅ alkylene, C₂-C₄ alkyleneoxy, C₁-C₃ alkylenedioxy, C₂-C₇alkanoyl, C₂-C₇ alkoxycarbonyl, piperidylcarbonyl, morpholinylcarbonyl,pyrrolidinylcarbonyl, piperazinylcarbonyl, C₂-C₇ alkanoyloxy, C₂-C₇alkanoylamino, C₁-C₆ alkylsulfonyl; C₃-C₈ (alkoxycarbonyl)methyl,mono(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, carbamoyl, C₂-C₇N-alkylcarbamoyl or C₄-C₉N-cycloalkylcarbamoyl groups for R⁴, R⁵, R⁶ andR⁷ have the same respective definitions as the substituents on R¹ or thesubstituents further substituting those substituents, and the samepreferred examples may be mentioned.

The term “C₄-C₁₀ cycloalkanoylamino” for R⁴, R⁵, R⁶ and R⁷ means a groupcomprising a C₄-C₁₀ cycloalkanoyl group and an amino group, and aspreferred examples there may be mentioned cyclopropanoylamino,cyclobutanoylamino, cyclopentanoylamino and cyclohexanoylamino.

The term “C₃-C₇ alkenoylamino” for R⁴, R⁵, R⁶ and R⁷ means a groupcomprising a C₃-C₇ alkenoyl group and an amino group, and as a preferredexample there may be mentioned acryloyl.

The term “C₁-C₆ alkylsulfonylamino” for R⁴, R⁵, R⁶ and R⁷ means a groupcomprising a C₁-C₆ alkylsulfonyl group and an amino group, and aspreferred examples there may be mentioned methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino and butylsulfonylamino.

The term “N—(C₇-C₁₂ phenylalkyl)carbamoyl” for R⁴, R⁵, R⁶ and R⁷ means agroup comprising a carbamoyl group and a C₇-C₁₂ phenylalkyl group, andas preferred examples there may be mentioned phenylmethylcarbamoyl andphenylethylcarbamoyl.

The term “C₁-C₆ N-alkylsulfamoyl” for R⁴, R⁵, R⁶ and R⁷ means a groupcomprising a C₁-C₆ alkyl group having the same definition as “C₁-C₆alkyl” as a substituent on R¹, and a sulfamoyl group, and as preferredexamples there may be mentioned N-methylsulfamoyl andN,N-dimethylsulfamoyl.

As particularly preferred groups for R⁴, R⁵, R⁶ and R⁷ there may bementioned halogens, hydroxy, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₂-C₇ alkoxycarbonyl, C₁-C₆ alkylsulfonyl and C₁-C₆ N-alkylsulfamoyl.

The C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₅ alkylene, C₃-C₈cycloalkyl, C₃-C₈ cycloalkenyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio,mono(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, C₃-C₇ lactam, C₂-C₇N-alkylcarbamoyl, C₄-C₉ N-cycloalkylcarbamoyl, N—(C₇-C₁₂phenylalkyl)carbamoyl or C₂-C₇ alkoxycarbonyl groups as substituents onR⁴, R⁵, R⁶ and R⁷ have the same respective definitions as thesubstituents on R¹, as the substituents further substituting thosesubstituents or as R⁴, R⁵, R⁶ and R⁷ themselves, and the same preferredexamples may be mentioned.

The term “(C₁-C₆ alkoxy) (C₁-C₆ alkoxy)” as a substituent on R⁴, R⁵, R⁶and R⁷ means a group comprising a C₁-C₆ alkoxy group and a C₁-C₆ alkoxygroup, and as preferred examples there may be mentioned methoxymethoxy,methoxyethoxy and ethoxyethoxy.

The term “phenyl(C₁-C₆ alkoxy)” as a substituent on R⁴, R⁵, R⁶ and R⁷means a group comprising a phenyl group and a C₁-C₆ alkoxy group, and aspreferred examples there may be mentioned benzyloxy, phenylethoxy andphenylpropoxy.

The term “(C₂-C₇ alkanoyl)piperidyl” as a substituent on R⁴, R⁵, R⁶ andR⁷ means a group comprising a C₂-C₇ alkanoyl group and a piperidylgroup, and as a preferred example there may be mentioned1-(acetyl)-4-piperidyl.

The number of substituents on the C₁-C₆ alkyl group for R⁸ and thenumber of substituents on the phenyl group as a substituent on the C₁-C₆alkyl group for R⁸ according to the invention may be any chemicallypossible number, but it is preferably 0-15, more preferably 0-10 andmore preferably 0-7.

The C₁-C₆ alkyl group for R⁸ has the same definition as the substituenton R¹, and the same preferred examples may be mentioned.

The halogen, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₂-C₇alkanoyl, C₂-C₇ alkoxycarbonyl, C₂-C₇ alkanoyloxy, C₂-C₇ alkanoylamino,C₂-C₇ N-alkylcarbamoyl, C₂-C₆ alkylsulfonyl, mono(C₁-C₆ alkyl)amino anddi(C₁-C₆ alkyl)amino groups as substituents on the C₁-C₆ alkyl group forR⁸ have the same respective definitions as the substituents of R¹, andthe same preferred examples may be mentioned.

The terms “halogen”, “C₁-C₆ alkyl” and “C₁-C₆ alkoxy” as substituents onthe phenyl group substituting the C₁-C₆ alkyl group of R⁸ have the samedefinitions as the substituents on R¹, and the same preferred examplesmay be mentioned.

As preferred examples of piperidine derivatives of formula (I) there maybe mentioned compounds containing the substituents listed in Tables 1 to8 below. The compound numbers are listed in the columns titled “Compnd.No.” in Tables 1 to 8.

Tables 1-1 to 1-6 list preferred examples of compounds wherein X=singlebond, q=0, r=0 and Y=—(R⁴)C═C(R⁵)—. Table 2 lists preferred examples ofcompounds wherein X=—CO—, q=0, r=0 and Y=—(R⁴)C═C(R⁵)—. Table 3 listspreferred examples of compounds wherein X=—SO₂—, q=0, r=0 andY=—(R⁴)C═C(R⁵)—. Table 4 lists preferred examples of compounds whereinX=—CH₂—, q=0, r=0 and Y=—(R⁴)C═C(R⁵)—. Table 5 lists preferred examplesof compounds wherein X=—CO—, q=0, r=0 and Y=—S—. Table 6 lists preferredexamples of compounds wherein X=—CO—, q=0, r=0 and Y=—N(R⁸)—. Table 7lists preferred examples of compounds wherein X=—CO—, q=1, r=0 andY=—(R⁴)C═C(R⁵)—. Table 8 lists preferred examples of compounds whereinX=—CS—, q=0, r=0 and Y=—(R⁴)C═C(R⁵)—. LENGTHY TABLE REFERENCED HEREUS20070032525A1-20070208-T00001 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070032525A1-20070208-T00002 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070032525A1-20070208-T00003 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070032525A1-20070208-T00004 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070032525A1-20070208-T00005 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070032525A1-20070208-T00006 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070032525A1-20070208-T00007 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070032525A1-20070208-T00008 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070032525A1-20070208-T00009 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070032525A1-20070208-T00010 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070032525A1-20070208-T00011 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070032525A1-20070208-T00012 Please refer to the end of thespecification for access instructions. LENGTHY TABLE REFERENCED HEREUS20070032525A1-20070208-T00013 Please refer to the end of thespecification for access instructions.

The present invention also encompasses pharmaceutically acceptable acidadducts of the aforementioned piperidine compounds. As examples ofsuitable acids there may be mentioned inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid andcarbonic acid, or organic acids such as maleic acid, citric acid, malicacid, tartaric acid, fumaric acid, methanesulfonic acid, trifluoroaceticacid and formic acid.

The invention further encompasses C₁-C₆ alkyl adducts of cyclic aminecompounds such as, for example,1-(4-chlorobenzyl)-1-methyl-4-[{2-benzimidazolyl}aminomethyl]piperidiniumiodide. As preferred examples of alkyl groups for C₁-C₆ alkyl adductsthere may be mentioned methyl, ethyl, n-propyl, n-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl,isopentyl, neopentyl, tert-pentyl, 2-methylpentyl and 1-ethylbutyl,among which methyl and ethyl are especially preferred. As preferredexamples of counter anions to the ammonium cation there may be mentionedhalide anions such as fluoride, chloride, bromide and iodide.

The compounds represented by formula (I) of the invention may containoptically active carbons, and therefore include racemic forms and allpossible optically active forms.

When R³ of the compound represented by formula (I) is hydrogen, thestructure represented by formula (I) will be indistinguishable from thestructure represented by formula (II) below, and formulas (I) and (II)will represent the same compound. When R³ is hydrogen, therefore, theinvention includes both the structures of formula (I) and formula (II).

The compounds represented by formula (I) may be produced by any of thegeneral production processes described below.

<Production Process 1>

One equivalent of a compound represented by the following formula (III):

(wherein R², R³, X, q, r, Y, R⁶ and R⁷ have the same definitions as informula (I))is treated with 0.1-10 equivalents of an alkylating reagent representedby the following formula (IV):R¹—(CH₂)_(p)-Z  (IV)(wherein R¹ and p have the same definitions as in formula (I), and Zrepresents a halogen, alkylsulfonyloxy or arylsulfonyloxy)in the presence or in the absence of a solvent, to produce a compoundrepresented by formula (I).

The reaction of Production Process 1 may be smoothly carried out using abase containing an inorganic salt such as potassium carbonate, calciumcarbonate or sodium hydrogen carbonate, an amine such as triethylamine,diisopropylethylamine or pyridine, or a polymer supporting base such as(piperidinomethyl)polystyrene, (morpholinomethyl)polystyrene,(diethylaminomethyl)polystyrene or poly(4-vinylpyridine).

The reaction of Production Process 1 will sometimes be accelerated byaddition of an iodide such as potassium iodide or sodium iodide.

The compounds of formula (III) may be synthesized by known processesdescribed in the relevant literature.

<Production Process 2>

One equivalent of an aldehyde represented by the following formula (V):R¹—(CH₂)_(p-1)CHO  (V)(where R¹ and p have the same respective definitions as in formula (I))is treated with 0.1-10 equivalents of a compound represented by formula(III), in the presence or in the absence of a solvent, to produce acompound represented by formula (I).

The reaction of Production Process 2 is generally referred to asreductive amination, and the reaction may be conducted under conditionswith a catalyst containing a metal such as palladium, platinum, nickelor rhodium, a hydride complex such as aluminum lithium hydride, sodiumborohydride, sodium cyanoborohydride or sodium triacetoxyborohydride,catalytic hydrogenation with borane, or electrolytic reduction.

<Production Process 3>

One equivalent of a compound represented by the following formula (VI):

(wherein R¹, p, R², R³, X, q and r have the same definitions as informula (I))is treated with 0.1-10 equivalents of a carboxylic acid or its reactivederivative, in the presence or in the absence of a solvent, to produce acompound represented by formula (I).

Reactive derivatives of carboxylic acids include highly reactivecarboxylic acid derivatives ordinarily used in organic syntheticchemistry, such as, for example, acid halides, acid anhydrides or mixedanhydrides.

The reaction of Production Process 3 may be smoothly carried out usingan appropriate amount of a dehydrating agent such as molecular sieve anda condensation agent such as dicyclohexylcarbodiimide (DCC),N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDCI or WSC),carbodiimidazole (CDI), N-hydroxysuccinimide (HOSu),N-hydroxybenzotriazole (HOBT),benzotriazol-1-yloxytris(pyrrolidino)phosphonium, hexafluorophosphate(PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU),2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU), 2-(5-norbornane-2,3-dicarboxyimide)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TNTU), O—(N-succinimidyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TSTU) or bromotris(pyrrolidino)phosphoniumhexafluorophosphate (PyBrop).

The reaction of Production Process 3 may be smoothly carried out using abase indicated for Production Process 1.

The compounds of formula (VI) may be synthesized by known processesdescribed in the relevant literature.

<Production Process 4>

One equivalent of a compound represented by the following formula (VII):

(wherein R¹, p, R², R³, X, q and r have the same definitions as informula (I))is treated with 0.1-10 equivalents of an amine, in the presence or inthe absence of a solvent, to produce a compound represented by formula(I).

The reaction of Production Process 4 can proceed smoothly by usingappropriate amounts of the same dehydrating agents, condensation agentsor bases used in Production Process 3.

The compounds of formula (VII) may be synthesized by known processesdescribed in the relevant literature.

<Production Process 5>

One equivalent of a compound represented by the following formula(VIII):

(wherein R¹, R² and p have the same definitions as in formula (I))is treated with 0.1-10 equivalents of an acid anhydride represented bythe following formula (IX):

(wherein R³, q and r have the same definitions as in formula (I), and Xrepresents CO)in the presence or in the absence of a solvent, to produce a compoundrepresented by formula (I).

The reaction of Production-Process 5 may be smoothly carried out using abase indicated for Production Process 1.

The compounds of formula (VIII) and (IX) may be synthesized by knownprocesses described in the relevant literature.

<Production Process 6>

One equivalent of a compound represented by the following formula (X):

(wherein R¹, R² and p have the same definitions as in formula (I))is treated with 0.1-10 equivalents of a sulfanyl or sulfinyl compoundrepresented by the following formula (XI):

(wherein R³, X, q and r have the same definitions as in formula (I), ands represents 0 or 1),in the presence or in the absence of a solvent, to produce a compoundrepresented by formula (I).

The reaction of Production Process 6 may be smoothly carried out using abase indicated for Production Process 1, or a suitable acid(hydrochloric acid, sulfuric acid, acetic acid, benzoic acid,toluenesulfonic acid, methanesulfonic acid or the like).

The compounds of formula (X) and (XI) may be synthesized by knownprocesses described in the relevant literature.

When the compounds of each of Production Processes 1-6 containfunctional groups which react with the substrates used under therespective reaction conditions or functional groups which generally canadversely affect reactions in organic synthetic chemistry, suchfunctional groups may be protected with appropriate known protectivegroups, and then subjected to the reaction of the production processesand subsequently deprotected using known steps, to obtain the compoundsof formula (I).

The compounds of the invention may also be produced by utilizing knownreactions ordinarily employed in organic synthetic chemistry, such asalkylation, acylation or reduction, for further conversion of (one ormore of) the substituents of the compounds produced by ProductionProcesses 1-6.

In each of Production Processes 1-6, the reaction may be conducted usinga halogenated carbon compound such as dichloromethane or chloroform, anaromatic hydrocarbon such as benzene or toluene, an ether such asdiethyl ether or tetrahydrofuran, an ester such as ethyl acetate, anaprotic polar solvent such as dimethylformamide, dimethylsulfoxide oracetonitrile, or an alcohol such as methanol, ethanol or isopropylalcohol.

In each of Production Processes 1-6 the reaction temperature is in therange of −78° C. and +150° C., and preferably between 0° C. and 100° C.Upon completion of the reaction, ordinary separation and purificationprocedures such as concentration, filtration, extraction, solid phaseextraction, recrystallization or chromatography may be employed toisolate the piperidine derivatives represented by formula (I). These maythen be converted to pharmaceutically acceptable acid adducts or C₁-C₆alkyl adducts by ordinary methods.

The compounds represented by formula (I), their pharmaceuticallyacceptable acid adducts or their pharmaceutically acceptable C₁-C₆ alkyladducts may be used in therapeutically effective doses together withpharmaceutically acceptable carriers and/or diluents for preparation ofpharmaceutical compositions, as drugs for inhibiting binding of CCR3ligands such as eotaxins to CCR3 on target cells, as drugs with activityof inhibiting the physiological effects of binding of CCR3 ligands suchas eotaxins to their target cells, and as therapeutic and/orprophylactic agents for diseases believed to be associated with CCR3.Specifically, the 4,4-piperidine derivatives represented by formula (I),their pharmaceutically acceptable acid adducts or their pharmaceuticallyacceptable C₁-C₆ alkyl adducts may be administered orally orparenterally, such as intravenously, subcutaneously, intramuscularly,percutaneously or intrarectally.

The dosage form for oral administration may be, for example, tablets,pills, granules, powder, a solution, a suspension, capsules or the like.

Tablets may be molded by an ordinary method using, for example, anexcipient such as lactose, starch or microcrystalline cellulose, abinder such as carboxymethyl cellulose, methyl cellulose orpolyvinylpyrrolidone and a disintegrator such as sodium alginate, sodiumhydrogen carbonate or lauryl sodium sulfate.

Pills, powders or granules may also be molded by ordinary methods usingthe aforementioned excipients and the like. Solutions and suspensionsmay be formed by ordinary methods using, for example, glycerin esterssuch as tricaprylin or triacetin and/or alcohols such as ethanol.Capsules may be prepared by filling capsules made of gelatin or the likewith granules, powders and/or solutions.

Dosage forms for subcutaneous, intramuscular or intravenousadministration include injections in the form of aqueous or non-aqueoussolutions. Aqueous solutions may employ, for example, physiologicalsaline. Non-aqueous solutions may employ, for example, propylene glycol,polyethylene glycol, olive oil or ethyl oleate, with addition ofantiseptic agents and/or stabilizers or the like as necessary.Injections are sterilized by appropriate filtration through abacteria-capturing filter or treatment with addition of a sterilizingagent.

As examples of dosage forms for percutaneous administration there may bementioned ointments and creams, among which ointments may be formedusing fats and oils such as castor oil or olive oil, or vaseline, andcreams may be formed by ordinary methods using emulsifying agents suchas fatty oils or diethylene glycol or sorbitan monofatty acid esters.

For intrarectal administration there may be used ordinary suppositoriessuch as gelatin soft capsules.

The dosage of a piperidine derivative of the invention, itspharmaceutically acceptable acid adduct or its pharmaceuticallyacceptable C₁-C₆ alkyl adduct will differ depending on the type ofdisease, the route of administration, the age and gender of the patientand the severity of the disease, but it will normally be 1-500 mg/dayper adult.

EXAMPLES

The present invention will now be explained in greater detail throughthe following examples. The invention, however, is not limited to theseexamples. The compound numbers referred to in the examples are thoseassigned to the compounds listed as preferred examples in the tables.The example numbers correspond to the compound numbers of the compoundsproduced in those examples.

Reference Example 1-1-1 Synthesis ofC-[1-(3,4-dichloro-benzyl)-piperidin-4-yl]-methylamine

After dissolving 4-aminomethyl-piperidine (10 g) in acetonitrile (250ml), 3,4-dichlorobenzyl chloride (5.8 g) and potassium carbonate (5 g)were added at room temperature, and the mixture was stirred at 60° C.overnight. The reaction mixture was filtered, the solvent was removedunder reduced pressure, and the obtained residue was purified bythin-layer silica gel chromatography(dichloromethane/methanol/triethylamine=85/7/7) to obtainC-[1-(3,4-dichloro-benzyl)-piperidin-4-yl]-methylamine. The compound wasidentified by LC-MS.

Yield: 6 g (75%), Purity: 100%, Found: ESI/MS m/e 273.2.

Reference Example 1-1-2 Synthesis of1-(2-amino-phenyl-3-[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-thiourea

After dissolving C-[1-(3,4-dichloro-benzyl)-piperidin-4-yl]-methylamine(80 mg) in acetonitrile (2 ml), thiocarbonyldiimidazole (80 mg) andimidazole (6 mg) were added at 0° C. The mixture was stirred at roomtemperature for 2 hours and 30 minutes, and then3-nitro-1,2-phenylenediamine (66 mg) was added and the temperature wasraised to 50° C. prior to stirring for 12 hours. The reaction mixturewas filtered, the solvent was removed under reduced pressure, and theobtained residue was purified by thin-layer silica gel chromatography(hexane/ethyl acetate/dichloromethane/methanol=60/25/10/5) to obtain1-(2-amino-phenyl-3-[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-thiourea.The compound was identified by LC-MS.

Yield: 75 mg (61%), Purity: 100%, Found: ESI/MS m/e 423.1.

Example 1-1-1 Synthesis of(1H-benzoimidazol-2-yl)-[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amine

After adding ethanol (1 ml) to1-(2-amino-phenyl-3-[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-thiourea(11 mg, 0.025 mmol), mercury (II) oxide red (16 mg, 0.074 mmol) andsulfur (0.3 mg, 0.0094 mmol) were added at room temperature, and themixture was refluxed for 7 hours. The mercury was filtered with celite,and the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography(hexane/dichloromethane/methanol/triethylamine=40/25/20/10/5) to obtain(1H-benzoimidazol-2-yl)-[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amine.The compound was identified by LC-MS.

Yield: 8 mg (83%), Purity: 100%, Found: ESI/MS m/e 389.1.

Example 1-1-2 to Example 1-1-11

Compound Nos. 1-1-2 to 1-1-11 were synthesized in the same manner asReference Example 1-1-1, Reference Example 1-1-2 and Example 1-1-1,using the corresponding starting materials. The results are shown inTable 9. TABLE 9 Compound No. 1-1- Yield (mg) Yield (%) MW M + 1 1 8 83389.3 389.1 2 30 68 434.3 434.2 3 13 32 403.4 403.2 4 5 12 423.8 423.1 57 16 407.3 407.1 6 13 28 457.3 457.2 7 4 9 433.3 433.2 8 23 50 458.2458.9 9 4 10 403.4 403.1 10 13 32 419.4 419.0 11 9 21 434.3 434.1

Reference Example 1-2-1 Synthesis of4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester

After dissolving 4-aminomethylpiperidine (5.00 g, 43.8 mmol) in toluene(90 mL), benzaldehyde (4.45 mL, 43.8 mmol) was added, a Dean-Stark trapwas fitted, and the mixture was heated to reflux for 2 hours. Thereaction mixture was cooled to room temperature, di-t-butyl dicarbonate(11.5 mL, 43.8 mmol) was added in 5 divided portions, and the mixturewas stirred at room temperature for 4 hours. After concentrating thereaction mixture under reduced pressure, an aqueous potassium hydrogensulfate solution (1.0 M, 70 mL, 70 mmol) was added in an ice bath, andthe mixture was vigorously stirred for 1 hour. It was then washed withdiethyl ether (30 mL×2 times), and 2N aqueous sodium hydroxide was addedto the aqueous layer to adjust the pH to approximately 7. The aqueoussolution was adjusted to a pH of approximately 7 and then washed withethyl acetate (30 mL×3 times), and 2N sodium hydroxide was added to theaqueous layer to adjust the pH to approximately 12. The aqueous solutionwas then adjusted to a pH of approximately 12 and extracted with ethylacetate (50 mL×4 times), after which the obtained organic layer wasdried over anhydrous magnesium sulfate. It was then concentrated underreduced pressure to obtain 4-aminomethyl-piperidine-1-carboxylic acidtert-butyl ester.

Yield: 6.49 g (70%).

Reference Example 1-2-2 Synthesis of4-[(1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylic acidtert-butyl ester

After dissolving 4-aminomethyl-piperidine-1-carboxylic acid tert-butylester (3.18 g, 14.8 mmol) in acetonitrile (20 mL), a suspension ofthiocarbonyldiimidazole (3.17 g, 17.8 mmol) and imidazole (302 mg, 4.45mmol) in acetonitrile (30 mL) was added dropwise thereto in an ice bath.The temperature was raised to room temperature, the mixture was stirredfor 90 minutes, o-phenylenediamine (1.93 g, 17.8 mmol) was addedthereto, and the mixture was stirred at 50° C. for 2 hours.Diisopropylcarbodiimide (3.4 mL, 22.2 mmol) was further added, and themixture was stirred at 80° C. for 3 hours. The mixture was cooled,concentrated under reduced pressure, and then dissolved in ethyl acetate(200 mL) and washed with water (100 mL×2 times) and brine (100 mL). Itwas then dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The concentrated residue was purified by silica gelcolumn chromatography (dichloromethane/methanol=19/1dichloromethane/methanol/triethylamine=10/1/1) to obtain4-[(1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylic acidtert-butyl ester.

Yield: 4.33 g (89%).

Reference Example 1-2-3 Synthesis of(1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine

After dissolving4-[(1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylic acidtert-butyl ester (4.33 g, 13.1 mmol) in methanol (10 mL), a 4N hydrogenchloride-1,4-dioxane solution (33 mL, 131 mmol) was added in smallportions at a time in an ice bath, and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was cooled on ice, 2Naqueous sodium hydroxide was added to adjust the pH to approximately 11.Salt was added to the aqueous solution to saturation, and the organiclayer obtained by extraction with 1-butanol (100 mL×3 times) was washedwith saturated brine and then dried over anhydrous sodium sulfate. Thedried 1-butanol was concentrated under reduced pressure to obtain(1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine.

Yield: 3.0 g (100%).

Example 1-2-1 Synthesis of(1H-benzimidazol-2-yl)-[1-(1-methyl-1H-indol-2-ylmethyl)-piperidin-4-ylmethyl]-amine

After adding 1-methyl-1H-indole-2-carboaldehyde (0.26 mmol) and sodiumtriacetoxyborohydride (0.26 mmol) to a solution of(1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine (20.0 mg, 0.09 mmol)in dimethylformamide-acetic acid (10:1) (1.0 ml), the mixture wasstirred at room temperature overnight. Methanol (1.0 ml) was added tothe reaction mixture to suspend the reaction, and after stirring for 1hour, the solution was passed through SCX (Bond Elute SCX500MG: cationicion-exchange resin, Varian). The SCX was washed with methanol and thenwith a mixed solution of chloroform/methanol (1/1), and elution wasperformed with a 2N ammonia-methanol solution. The solvent was distilledoff under reduced pressure to obtain(1H-benzimidazol-2-yl)-[1-(1-methyl-1H-indol-2-ylmethyl)-piperidin-4-ylmethyl]-amine.The compound was identified by LC-MS.

Yield: 18 mg (54%), Purity: 86%, Found: ESI/MS m/e 374.2 (M+1).

Example 1-2-2 to Example 1-2-169

Compound Nos. 1-2-2 to 1-2-169 were synthesized in the same manner asExample 1-2-1, using the corresponding starting materials. The resultsare shown in Table 10.

Reference Example 1-2-4 Synthesis of 4-phenylbutylaldehyde

After adding molecular sieves MS4A (desiccant, trade name of Wako PureChemical Industries) (451.5 mg) to a solution of pyridinium dichromate(451.5 mg, 1.20 mmol) in dichloromethane (3.33 ml), the mixture wasstirred for 1 hour. Next, 4-phenylbutanol (154 μl, 1.00 mmol) was addedto the suspension and the mixture was stirred at room temperature for1.5 hours. The reaction suspension was filtered with silica gel, and thefiltrate was concentrated under reduced pressure to obtain4-phenylbutylaldehyde.

Yield: 38.45 mg (26%).

Example 1-2-170 Synthesis of(1H-benzimidazol-2-yl)-[1-(4-phenyl-butyl)-piperidin-4-ylmethyl]-amine

After adding acetic acid (28.6 μl) and sodium triacetoxyborohydride(52.99 mg, 0.25 mmol) to a mixed solution of(1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine (30.32 mg, 0.10 mmol)and a mixed solution of the obtained 4-phenylbutylaldehyde (38.45 mg) indichloroethane (1.0 ml) and dimethylformamide (0.5 ml), the mixture wasstirred at room temperature overnight. The reaction suspension waspassed through SCX (Bond Elute SCX500MG), and the SCX was washed with amixed solution of chloroform-methanol (1:1). This was followed byelution with a 2N ammonia-methanol solution, and the solvent was thendistilled off under reduced pressure to obtain a residue. The residuewas purified by preparative HPLC to obtain(1H-benzimidazol-2-yl)-[1-(4-phenyl-butyl)-piperidin-4-ylmethyl]-amine.The compound was identified by LC-MS.

Yield: 19.44 mg (54%), Purity: 89.8%, Found: ESI/MS m/e 363.2 (M+1).

Example 1-2-171

Compound No. 1-2-171 was synthesized in the same manner as Example1-2-170, using an aldehyde starting material synthesized according toReference Example 1-2-4. The results are shown in Table 10.

Example 1-2-172 Synthesis of(1H-benzimidazol-2-yl)-[1-(6-methoxy-1-methyl-1H-indol-3-ylmethyl)-piperidin-4-ylmethyl]-amine

After adding anhydrous acetonitrile (2 ml) to a mixture of(1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine (20 mg, 0.09 mmol),(6-methoxy-1-methyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (0.1mmol) and anhydrous potassium carbonate (5 mg, 0.11 mmol), the mixturewas stirred at 50° C. for 12 hours. The mixture was cooled to roomtemperature and then passed through a silica gel short column andpurified by preparative HPLC to obtain(1H-benzimidazol-2-yl)-[1-(6-methoxy-1-methyl-1H-indol-3-ylmethyl)-piperidin-4-ylmethyl]-amine.The compound was identified by LC-MS.

Yield: 5.66 mg (13%), Purity: 96.3%, Found: ESI/MS m/e 404.4 (M+1).

Example 1-2-173 to Example 1-2-180

Compound Nos. 1-2-173 to 1-2-180 were synthesized according to Example1-2-172, from the corresponding halides or quaternary ammonium halides.The results are shown in Table 10. TABLE 10 Compound No. 1-2- Yield (mg)Yield (%) MW M + 1 1 18 54 373.5 374.2 2 29 54 370.5 371.2 3 11 41 320.4321.2 4 23 76 354.9 355.2 5 9 29 334.5 335.2 6 28 82 388.4 389.2 7 23 74362.5 363.2 8 21 71 345.4 346.2 9 33 96 398.5 399.2 10 16 48 378.5 379.211 21 68 350.5 351.2 12 16 82 326.5 327.2 13 8 40 334.5 335.2 14 19 91348.5 349.3 15 25 78 359.5 360.2 16 18 54 373.5 374.2 17 12 42 310.4311.2 18 21 70 326.5 327.1 19 22 62 390.6 391.2 20 14 48 321.4 322.2 2115 53 321.4 322.2 22 15 46 371.5 372.2 23 14 41 371.5 372.2 24 17 57327.5 328.1 25 21 75 310.4 311.2 26 22 79 310.4 311.2 27 24 65 414.6415.2 28 6 17 413.6 414.2 29 23 69 374.5 375.2 30 20 70 334.5 335.6 3115 50 345.4 346.5 32 22 63 396.5 397.2 33 21 68 350.5 351.2 34 18 58354.9 355.3 35 15 43 389.3 389.4 36 21 68 354.9 355.3 37 16 51 365.4366.3 38 15 45 388.4 389.4 39 15 43 399.3 399.1 40 16 54 334.5 335.4 4115 53 336.4 337.2 42 22 74 336.4 337.2 43 13 41 363.5 364.2 44 18 54377.5 378.2 45 21 68 364.5 365.2 46 11 33 378.5 379.2 47 15 46 378.5379.2 48 17 45 426.6 427.2 49 23 63 426.6 427.2 50 22 69 370.5 371.4 5121 66 364.5 365.3 52 18 57 360.5 361.2 53 21 57 420.9 421.5 54 21 55396.5 397.4 55 7 20 388.5 389.3 56 10 41 403.5 404.2 57 3 13 387.5 388.258 22 100 338.4 339.2 59 22 67 321.4 322.2 60 19 56 338.4 339.1 61 24 68350.5 351.2 62 23 100 378.5 379.2 63 30 100 412.5 413.2 64 17 70 404.4405.1 65 28 100 389.3 389.1 66 14 57 406.4 407.1 67 30 83 364.4 365.1 6820 43 456.4 457.1 69 28 78 352.4 353.2 70 29 69 412.5 413.2 71 33 78426.6 427.2 72 34 86 399.3 400.1 73 28 82 345.4 346.2 74 24 54 442.6443.2 75 25 68 365.4 366.2 76 35 81 426.6 427.2 77 26 57 447.0 447.2 7828 72 380.5 381.2 79 22 58 380.5 381.2 80 17 78 362.5 363.2 81 20 90370.9 371.1 82 20 90 372.9 373.1 83 19 69 456.6 457.2 84 8 32 417.3417.1 85 12 47 429.4 429.2 86 17 69 408.5 409.3 87 18 79 381.4 382.2 8820 87 381.4 382.2 89 11 46 399.9 400.1 90 20 88 378.5 379.2 91 16 73364.4 365.2 92 15 58 430.5 431.3 93 16 67 400.5 401.3 94 20 81 413.6414.3 95 12 50 400.5 401.3 96 13 52 414.6 415.3 97 19 78 408.5 409.3 9822 62 350.5 351.5 99 10 27 380.4 381.2 100 29 80 366.5 367.1 101 3 6456.6 457.3 102 13 37 352.4 353.2 103 15 40 366.5 367.2 104 15 56 449.4450.2 105 15 61 410.5 411.3 106 16 69 389.3 389.2 107 11 51 356.4 357.2108 10 39 422.9 423.2 109 10 41 406.4 407.2 110 2 8 392.5 393.7 111 4 15395.5 396.3 112 6 27 359.5 360.3 113 16 47 376.5 377.3 114 19 50 420.6421.4 115 4 11 420.6 421.4 116 14 40 401.5 402.4 117 17 54 370.9 371.2118 14 39 415.3 417.1(Br) 119 8 25 381.4 382.2 120 7 21 383.4 384.2 12110 32 354.4 355.2 122 6 17 392.5 393.3 123 18 56 368.5 369.2 124 22 61417.3 419.1(Br) 125 26 69 429.4 429.2 126 21 67 366.5 367.3 127 27 85443.4 445.2(Br) 128 23 66 399.9 400.2 129 31 91 394.5 395.3 130 20 61370.4 371.2 131 30 91 372.9 373.2 132 22 60 422.6 423.2 133 22 70 364.5365.2 134 22 72 352.5 353.2 135 19 57 399.9 400.1 136 24 74 378.5 379.2137 3 91 420.4 421.3 138 11 35 348.5 349.3 139 10 28 424.5 425.3 140 825 380.5 381.2 141 20 51 455.6 456.3 142 13 37 404.6 405.3 143 13 38389.3 389.1 144 17 43 450.5 451.3 145 20 58 400.5 401.3 146 24 63 437.6438.3 147 21 61 390.6 391.2 148 5 17 336.4 337.1 149 11 33 364.4 365.1150 7 19 405.3 405.1 151 2 6 386.5 387.1 152 5 14 386.5 387.1 153 1 4428.5 429.2 154 8 8 369.9 370.1 155 6 20 365.4 366.1 156 5 16 365.4366.1 157 6 20 338.4 366.1 158 10 12 335.5 336.1 159 11 29 420.5 421.1160 9 23 462.3 463.1 161 17 53 364.4 365.1 162 10 26 449.8 451.0(Br) 16323 23 371.5 372.1 164 17 17 386.4 387.1 165 7 20 384.9 385.1 166 5 10588.2 589.0 167 14 38 438.9 439.2 168 9 23 438.9 439.1 169 15 46 370.9371.1 170 19 54 362.5 363.2 171 31 82 376.5 377.3 172 6 13 403.5 404.4173 3 8 387.5 388.3 174 6 18 387.5 388.2 175 23 70 384.5 385.2 176 9 27384.5 385.2 177 8 22 401.6 402.3 178 5 13 387.5 388.2 179 7 20 387.5388.4 180 2 5 449.6 450.5

Reference Example 1-3-1 Synthesis of4-[(4-nitro-1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester

After dissolving 4-aminomethyl-piperidine-1-carboxylic acid tert-butylester (2 g) in acetonitrile (100 ml), thiocarbonyldiimidazole (2 g) andimidazole (0.2 g) were added at 0° C. The mixture was stirred at roomtemperature for 2 hours and 30 minutes, 3-nitro-1,2-phenylenediamine(2.1 g) was added, the temperature was raised to 50° C., and the mixturewas stirred for 12 hours. Diisopropylcarbodiimide (2.4 g) was added, themixture was refluxed for 3 hours and 30 minutes, and then the solventwas removed under reduced pressure and the obtained residue was purifiedby silica gel chromatography (dichloromethane/hexane=7/3→1/0) to obtain4-[(4-nitro-1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester. The compound was identified by LC-MS.

Yield: 3.5 g (100%), Purity: 95%, Found: ESI/MS m/e 376.4 (M+1).

Reference Example 1-3-2 Synthesis of(4-nitro-1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine

After dissolving4-[(4-nitro-1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (13 mg) in methanol (1 ml), a 4N hydrogenchloride-1,4-dioxane solution (1 ml) was added and the mixture wasstirred at 60° C. for 1 hour. The solvent was distilled off underreduced pressure, aqueous sodium hydroxide and dichloromethane wereadded to the obtained residue, and extraction was performed withdichloromethane. The solvent was distilled off under reduced pressure toobtain (4-nitro-1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine. Thecompound was identified by LC-MS.

Yield: 8 mg (83%), Purity: 100%, Found: ESI/MS m/e 276.1 (M+1).

Reference Example 1-3-3 Synthesis of(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(4-nitro-1H-benzimidazol-2-yl)-amine

After adding 1-naphthoaldehyde (3 mmol) and sodium triacetoxyborohydride(3 mmol) to a solution of(4-nitro-1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine (450 mg, 1mmol) in dimethylformamide-acetic acid (10:1) (7 mL), the mixture wasstirred at room temperature overnight. Water and dichloromethane wereadded, and extraction was performed with dichloromethane. The solventwas removed under reduced pressure, and the residue was purified bysilica gel column chromatography (ethylacetate/triethylamine=100/0→98/2) to obtain(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(4-nitro-1H-benzimidazol-2-yl)-amine.The compound was identified by LC-MS.

Yield: 500 mg (100%), Purity: 100%, Found: ESI/MS m/e 394.0 (M+1).

Reference Example 1-3-4 Synthesis of4-amino-2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-benzimidazole-1-carboxylicacid tert-butyl ester

After dissolving(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(4-nitro-1H-benzimidazol-2-yl)-amine(500 mg) in 1,4-dioxane (15 ml), di-t-butyl dicarbonate (1 g) was addedand the mixture was stirred at 50° C. for 2 hours. The solvent wasremoved under reduced pressure, and the obtained residue was washed withhexane (5 ml×5 times). The residue was dissolved in tetrahydrofuran (10ml), Raney nickel (500 mg) was added, and the mixture was stirred atroom temperature overnight under a hydrogen stream. The reaction mixturewas filtered with celite, and then the solvent was distilled off underreduced pressure to obtain4-amino-2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-benzimidazole-1-carboxylicacid tert-butyl ester.

The compound was identified by LC-MS.

Yield: 200 mg (39%), Purity: 100%, Found: ESI/MS m/e 464.3 (M+1).

Example 1-3-1 Synthesis of3-acetylamino-N-{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-4-yl}-propionamide

After dissolving4-amino-2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-benzimidazole-1-carboxylicacid tert-butyl ester (0.02 mmol) in tetrahydrofuran (1 ml),diisopropylcarbodiimide (0.05 mmol), 1-hydroxybenzotriazole monohydrate(0.05 mmol) and 3-acetylaminopropionic acid (0.05 mmol) were added andthe mixture was stirred at room temperature overnight. After adding a 4Nhydrogen chloride-1,4-dioxane solution (1 ml) to the reaction mixture,it was stirred at 50° C. for 1 hour, the solvent was removed underreduced pressure, and then dichloromethane and 5N aqueous sodiumhydroxide were added to the obtained residue prior to stirring. Theorganic layer was passed through SCX (Bond Elute SCX500MG), and afterwashing the SCX with methanol, elution was performed with a 2Nammonia-methanol solution. The solvent was distilled off under reducedpressure to obtain3-acetylamino-N-{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-4-yl}-propionamide.The compound was identified by LC-MS.

Yield: 0.4 mg (4%), Purity: 100%, Found: ESI/MS m/e 499.3 (M+1).

Example 1-3-2 to Example 1-3-8

Compound Nos. 1-3-2 to 1-3-8 were synthesized in the same manner asReference Examples 1-3-1 to 1-3-4 and Example 1-3-1, using thecorresponding starting materials. The results are shown in Table 11.

Example 1-3-9 Synthesis ofN-(2-{[1-(3,4-dichlorobenzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazol-4-yl)-butylamide

After dissolving4-amino-2-{[1-(3,4-dichlorobenzyl)-piperidin-4-ylmethyl]-amino}-benzimidazole-1-carboxylicacid tert-butyl ester (10 mg, 0.02 mmol) in tetrahydrofuran (1 ml),triethylamine (5.6 μl, 0.04 mmol) and butyryl chloride (8.3 μl, 0.08mmol) were added and the mixture was stirred at room temperature for 1hour and 30 minutes. After adding a 4N hydrogen chloride-1,4-dioxanesolution (1 ml) to the reaction mixture, it was stirred at 50° C. for 2hours. The solvent was removed under reduced pressure, dichloromethaneand 5N aqueous sodium hydroxide were added to the obtained residue, andafter stirring, the organic layer was passed through SCX (Bond EluteSCX500MG). The SCX was washed with methanol and elution was performedwith a 2N ammonia-methanol solution. The solvent was distilled off underreduced pressure to obtainN-(2-{[1-(3,4-dichlorobenzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazol-4-yl)-butylamide.The compound was identified by LC-MS.

Yield: 4.9 mg (52%), Purity: 100%, Found: ESI/MS m/e 474.0 (M+1).

The4-amino-2-{[1-(3,4-dichlorobenzyl)-piperidin-4-ylmethyl]-amino}-benzimidazole-1-carboxylicacid tert-butyl ester starting material was synthesized in the samemanner as Reference Examples 1-3-1 to 1-3-4, using the correspondingstarting materials.

Example 1-3-10 to Example 1-3-56

Compound Nos. 1-3-10 to 1-3-56 were synthesized in the same manner asExample 1-3-9, using the corresponding starting materials. The resultsare shown in Table 11.

Example 1-3-57 Synthesis of propane-1-sulfonic acid(2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazol-4-yl)-amide

After dissolving4-amino-2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-benzimidazole-1-carboxylicacid tert-butyl ester (10 mg, 0.02 mmol) in tetrahydrofuran (1 ml),triethylamine (0.04 mmol) and propane-1-sulfonyl chloride (0.08 mmol)were added and the mixture was stirred at room temperature overnight.After adding a 4N hydrogen chloride-1,4-dioxane solution (1 ml) to thereaction mixture, it was stirred at 50° C. for 1 hour. The solvent wasremoved under reduced pressure, dichloromethane and 5N aqueous sodiumhydroxide were added to the obtained residue, and after stirring, theorganic layer was passed through SCX (Bond Elute SCX500MG). The SCX waswashed with methanol and elution was performed with a 2Nammonia-methanol solution. The solvent was distilled off under reducedpressure to obtain propane-1-sulfonic acid(2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazol-4-yl)-amide.The compound was identified by LC-MS.

Yield: 0.8 mg (8%), Purity: 100%, Found: ESI/MS m/e 510.1 (M+1).

Example 1-3-58

Compound No. 1-3-58 was synthesized in the same manner as Example1-3-57, using the corresponding starting materials. The results areshown in Table 11.

Example 1-3-59 Synthesis of1-(2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazol-4-yl)-3-ethyl-urea

After dissolving4-amino-2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-benzimidazole-1-carboxylicacid tert-butyl ester (10 mg, 0.02 mmol) in acetonitrile (1 ml), ethylisocyanate (0.08 mmol) was added and the mixture was stirred at roomtemperature overnight. After adding a 4N hydrogen chloride-1,4-dioxanesolution (1 ml) to the reaction mixture, it was stirred at 50° C. for 1hour and then the reaction mixture was passed through SCX (Bond EluteSCX500MG). The SCX was washed with methanol and elution was performedwith a 2N ammonia-methanol solution. The solvent was distilled off underreduced pressure to obtain1-(2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazol-4-yl)-3-ethyl-urea.The compound was identified by LC-MS.

Yield: 1.6 mg (17%), Purity: 96%, Found: ESI/MS m/e 475.1 (M+1).

Example 1-3-60

Compound No. 1-3-60 was synthesized in the same manner as Example1-3-59, using the corresponding starting materials. The results areshown in Table 11.

Example 1-3-61 Synthesis ofN2-[1-(3,4-dichlorobenzyl)-piperidin-4-ylmethyl]-1H-benzimidazole-2,4-diamine

After dissolving4-amino-2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-benzimidazole-1-carboxylicacid tert-butyl ester (10 mg, 0.02 mmol) in methanol (1 ml), a 4Nhydrogen chloride-1,4-dioxane solution (1 ml) was added and the mixturewas stirred at 50° C. for 1 hour. The reaction mixture was passedthrough SCX (Bond Elute SCX500MG), the SCX was washed with methanol, andthen elution was performed with a 2N ammonia-methanol solution. Thesolvent was distilled off under reduced pressure to obtainN2-[1-(3,4-dichlorobenzyl)-piperidin-4-ylmethyl]-1H-benzimidazole-2,4-diamine.The compound was identified by LC-MS.

Yield: 6.5 mg (80%), Purity: 100%, Found: ESI/MS m/e 404.1 (M+1).

Example 1-3-62

Compound No. 1-3-62 was synthesized in the same manner as Example1-3-61, using the corresponding starting materials. The results areshown in Table 11. TABLE 11 Compound No. 1-3- Yield (mg) Yield (%) MWM + 1 1 0.4 4 498.6 499.3 2 2 24 490.4 489.9 3 4 39 462.6 463.3 4 5 50476.6 477.1 5 1 12 484.6 485.4 6 2 23 499.0 499.1 7 3 29 490.4 490.1 8 330 475.4 475.1 9 5 52 474.4 474.0 10 4 16 488.5 488.4 11 4 12 565.5565.4 12 4 14 557.5 557.5 13 24 92 520.5 520.4 14 1 3 551.5 551.5 15 39100 514.5 514.4 16 2 8 499.4 499.4 17 28 100 509.4 509.5 18 30 100 506.5506.4 19 3 11 488.5 488.4 20 1 4 546.5 546.4 21 30 100 509.4 509.5 22 31100 509.4 509.5 23 29 100 552.5 552.4 24 1 4 553.4 553.4 25 14 53 528.5528.4 26 17 67 514.5 514.4 27 2 8 498.4 498.4 28 19 73 514.5 514.4 29 1557 528.5 528.4 30 17 68 500.5 500.5 31 4 15 486.4 486.4 32 21 89 472.4472.4 33 20 86 460.4 460.4 34 40 100 458.4 458.4 35 16 66 476.4 476.3 3619 69 552.5 538.4 37 19 80 474.4 474.2 38 19 76 488.5 488.3 39 19 71522.5 522.5 40 1 4 538.5 538.4 41 3 11 542.9 542.4 42 17 65 508.5 508.443 5 22 446.4 446.1 44 7 68 518.4 518.0 45 8 76 522.5 522.0 46 9 88536.5 536.3 47 2 6 504.4 504.0 48 2 7 503.4 503.3 49 3 10 476.4 476.0 502 6 475.4 475.2 51 5 19 517.5 517.1 52 6 67 446.4 446.1 53 6 55 536.5536.3 54 5 47 474.4 474.0 55 2 23 522.5 522.0 56 1 10 504.4 503.9 57 1 8510.5 510.1 58 4 37 510.5 510.2 59 2 17 475.4 475.1 60 2 17 475.4 475.061 7 80 404.3 404.1 62 9 72 404.3 404.1

Reference Example 1-4-1 Synthesis of 3-nitrophthalic acid

4-nitroisobenzofuran-1,3-dione (20.0 g, 0.104 mol) was added in smallportions at a time to an aqueous ammonia solution (28%, 28 ml) heated to50° C. After stirring for 30 minutes, the reaction mixture was cooled onice, and the precipitate was filtered out and dried to obtain anammonium salt. The salt was suspended in water (40 ml), and thenconcentrated hydrochloric acid was added dropwise to adjust the pH toapproximately 2. The precipitated solid was filtered and dried to obtain3-nitrophthalic acid. The compound was identified by NMR.

Yield: 12.3 g (56%).

¹H-NMR (270 MHz, CD₃OD): δ8.28(1H, dd, J=7.6, 1.2 Hz), 8.25 (1H, dd,J=7.8, 1.2 Hz), 7.72(1H, dd, J=7.8, 7.6 Hz) ppm.

Reference Example 1-4-2 Synthesis of 2-amino-3-nitrobenzoic acid

Potassium hydroxide (4.27 g, 76.2 mmol) was dissolved in water (22 ml),and bromine (0.463 ml, 9.50 mmol) was added dropwise while cooling onice. After adding 3-nitrophthalic acid (2.00 g, 9.52 mmol) to thoroughdissolution, the mixture was stirred at 60° C. for 3 hours, and stirringwas continued overnight at room temperature. The reaction mixture wascooled on ice, and an orange precipitate was filtered out. It was thendissolved in 20 ml of water, and concentrated hydrochloric acid wasadded dropwise to adjust the pH to 4. After cooling on ice, the yellowprecipitate was filtered out and dried to obtain 2-amino-3-nitrobenzoicacid. The compound was identified by NMR.

Yield: 1.03 g (59%).

¹H-NMR (270 MHz, CD₃OD): δ8.33(1H, dd, J=8.4, 1.7 Hz), 8.27(1H, dd,J=7.6, 1.7 Hz), 6.67(1H, dd, J=8.7, 7.6 Hz) ppm.

Reference Example 1-4-3 Synthesis of 2-amino-3-nitrobenzoic acid methylester

After dissolving 2-amino-3-nitrobenzoic acid (1.00 g, 5.49 mmol) inmethanol (40 ml), sulfuric acid (0.50 ml) was added and the mixture washeated to reflux for 2 days. The reaction mixture was cooled to roomtemperature, and then the pH was adjusted to approximately 9 withsaturated aqueous sodium bicarbonate and the mixture was concentratedunder reduced pressure to approximately 10 ml. Water (20 ml) was added,the mixture was extracted with ethyl acetate (10 ml×3 times), and theobtained organic layer was dried over anhydrous magnesium sulfate. Itwas then concentrated under reduced pressure, and the produced crystalswere dried to obtain 2-amino-3-nitrobenzoic acid methyl ester. Thecompound was identified by NMR.

Yield: 661.4 mg (61%).

¹H-NMR (270 MHz, CDCl₃): δ8.50(br), 8.37(1H, dd, J=8.6, 1.4 Hz),8.23(1H, dd, J=7.6, 1.4 Hz), 6.65(1H, dd, J=8.6, 7.6 Hz), 3.92(3H, s)ppm.

Reference Example 1-4-4 Synthesis of 2,3-diaminobenzoic acid methylester

After dissolving 2-amino-3-nitrobenzoic acid methyl ester (661 mg, 3.37mmol) in methanol (30 ml), 10% palladium-carbon powder (5 mol %) wasadded under a nitrogen stream, and the mixture was stirred for 1 hourunder a hydrogen atmosphere. The reaction mixture was filtered throughcelite, and the obtained filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(n-hexane/ethyl acetate=2/1) to obtain 2,3-diaminobenzoic acid methylester. The compound was identified by NMR.

Yield: 517.2 mg (92%).

¹H-NMR (270 MHz, CDCl₃): δ7.46(1H, dd, J=8.2 Hz, 1.5 Hz), 6.85(1H, dd,J=8.2 Hz, 1.5 Hz), 6.60(1H, t, J=8.2 Hz), 5.53(br), 3.87(3H, s),3.35(br) ppm.

Reference Example 1-4-5 Synthesis of2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylicacid methyl ester

After dissolving 4-aminomethyl-piperidine-1-carboxylic acid tert-butylester (3.29 g, 15.4 mmol) in acetonitrile (40 ml), the mixture wascooled in an ice bath. A solution of 1,1-thiocarbonyldiimidazole (3.28g, 18.4 mmol) and imidazole (314 mg, 4.6 mmol) in acetonitrile (30 ml)was added dropwise thereto, and the mixture was stirred for 2 hourswhile raising the temperature to room temperature. After adding2,3-diaminobenzoic acid methyl ester (3.07 g, 18.5 mmol) to the reactionmixture, it was stirred at 50° C. overnight. Diisopropylcarbodiimide(2.84 ml, 18.5 mmol) was then added and the mixture was stirred at 80°C. for 2 hours. The residue obtained by concentrating the reactionmixture under reduced pressure was purified by silica gel columnchromatography (n-hexane/ethyl acetate=3/2→ethylacetate/methanol/triethylamine=10/1/0.1) to obtain2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylicacid methyl ester. The compound was identified by LC-MS.

Yield: 5.47 g (91.4%), [M+1]=389.2.

Reference Example 1-4-6 Synthesis of2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acidmethyl ester

After dissolving2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylicacid methyl ester (2.28 g, 5.87 mmol) in methanol (3 ml), a 4N hydrogenchloride-1,4-dioxane solution (10 ml, 40 mmol) was added and the mixturewas stirred at room temperature overnight. The precipitated crystalswere filtered out, washed with ethyl acetate and then dried to obtain2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acidmethyl ester. The compound was identified by LC-MS.

Yield: 1.19 g (56.1%), [M+1]=289.2.

Example 1-4-1 Synthesis of2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylicacid methyl ester

After dissolving2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acidmethyl ester (20 mg, 0.055 mmol) in dimethylsulfoxide-acetic acid(10:1), 2-hydroxy-3,5-dichlorobenzaldehyde (32.0 mg, 0.166 mmol) andsodium triacetoxyborohydride (35.0 mg, 0.166 mg) were added and themixture was stirred at 50° C. for 2 days. Methanol (1 ml) was added tothe reaction mixture, and then after stirring for 1 minute, it waspurified by SCX solid phase extraction (Bond Elute SCX500MG). Theproduct was further purified by preparative HPLC to obtain2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylicacid methyl ester. The compound was identified by LC-MS.

Yield: 10.1 mg (39.3%), Purity: 94.0%, [M+1]=463.1

Example 1-4-2 to Example 1-4-9

Compound Nos. 1-4-2 to 1-4-9 were synthesized in the same manner asExample 1-4-1, using the corresponding starting materials. The resultsare shown in Table 12.

Reference Example 1-4-7 Synthesis of2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylicacid

After dissolving2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylicacid methyl ester (5.47 g, 14.1 mmol) in methanol (60 ml), an aqueouslithium hydroxide solution (4 mol/L, 20 ml, 80 mmol) was added and themixture was stirred at 50° C. overnight. The reaction mixture was cooledin an ice bath, and 6N hydrochloric acid (5 ml) was added dropwise.Stirring was continued for 1 hour in an ice bath while gradually adding1N hydrochloric acid to adjust the pH to approximately 7.5. Theprecipitate was filtered out and washed with ethyl acetate and water. Itwas then dried under reduced pressure to obtain2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethlyl)-amino]-1H-benzimidazole-4-carboxylicacid. The compound was identified by LC-MS.

Yield: 3.68 g (69.7%), [M+1]=375.2.

Reference Example 1-4-8 Synthesis of4-{[4-(2-methoxy-ethylcarbamoyl)-1H-benzimidazol-2-ylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester

After suspending2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylicacid (1.20 g, 3.20 mmol) in a mixed solvent of dimethylformamide andtetrahydrofuran (1:1, 20 ml), 1-hydroxybenzotriazole monohydrate (737mg, 4.81 mmol) and 2-methoxyethylamine (0.42 ml, 4.8 mmol) were added.1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.90 g,6.40 mmol) was further added, and then the mixture was stirred at roomtemperature for 4 hours. Water (100 ml) was added to the reactionmixture, extraction was preferred with ethyl acetate (150 ml×3 times),and the organic layer was washed with saturated brine (100 ml) and thendried over anhydrous magnesium sulfate. The residue obtained byconcentrating this under reduced pressure was purified by silica gelcolumn chromatography (ethyl acetate/methanol=30/1) to obtain4-{[4-(2-methoxy-ethylcarbamoyl)-1H-benzimidazol-2-ylamino)-methyl}-piperidine-1-carboxylicacid tert-butyl ester. The compound was identified by LC-MS.

Yield: 1.30 g (94.1%), Purity: [M+1]=432.2.

Reference Example 1-4-9 Synthesis of2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid(2-methoxy-ethyl)-amide

After dissolving4-{[4-(2-methoxy-ethylcarbamoyl)-1H-benzimidazol-2-ylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester (1.30 g, 3.01 mmol) in methanol (1 ml), a 4Nhydrogen chloride-1,4-dioxane solution (7.0 ml, 28.0 mmol) was added andthe mixture was stirred at 50° C. for 1 hour. The reaction mixture wasconcentrated under reduced pressure and vacuum dried to obtain2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid(2-methoxy-ethyl)-amide. The compound was identified by LC-MS.

Yield: 1.23 g (100%), Purity: [M+1]=332.2.

Example 1-4-10 Synthesis of2-{[1-(5-chloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylicacid (2-methoxy-ethyl)-amide

After dissolving2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid(2-methoxy-ethyl)-amide (20 mg, 0.049 mmol) in dimethylsulfoxide-aceticacid (10:1, 0.50 ml), 2-hydroxy-5-chlorobenzaldehyde (23 mg, 0.15 mmol)and sodium triacetoxyborohydride (31 mg, 0.15 mg) were added and themixture was stirred at 50° C. for 2 days. Methanol (1 ml) was added tothe reaction mixture, and after stirring for 1 minute, the mixture waspurified by SCX solid phase extraction (Bond Elute SCX500MG). Theproduct was further purified by preparative HPLC to obtain2-{[1-(5-chloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylicacid (2-methoxy-ethyl)-amide. The compound was identified by LC-MS.

Yield: 9.4 mg (40.6%), Purity: 94.0%, [M+1]=472.2.

Example 1-4-11 to Example 1-4-17

Compound Nos. 1-4-11 to 1-4-17 were synthesized in the same manner asExample 1-4-10, using the corresponding starting materials. The resultsare shown in Table 12.

Reference Example 1-4-10 Synthesis of2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylicacid

After suspending2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylicacid methyl ester (993 mg, 2.14 mmol) in methanol (10 ml), an aqueouslithium hydroxide solution (4M, 5.4 ml, 21.4 mmol) was added. Thereaction mixture was stirred at 50° C. for 2 hours and then cooled toroom temperature. 1N hydrochloric acid was added dropwise to adjust thepH to approximately 6.0. Ethyl acetate (1 ml) was then added and themixture was stirred for 3 hours, after which the precipitate wasfiltered out to obtain2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylicacid. The compound was identified by LC-MS.

Yield: 802.6 mg (83.5%), [M+1]=449.1.

Example 1-4-18 Synthesis of2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylicacid isopropylamide

2-{[1-(3,5-Dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylicacid (30.0 mg, 0.0668 mmol) was suspended in dimethylformamide (0.50ml). After adding 1-hydroxybenzotriazole monohydrate (30.6 mg, 0.200mmol), isopropylamine (11.8 mg, 0.200 mmol) and diisopropylcarbodiimide(30.8 μl, 0.200 mmol) thereto, the mixture was stirred at 40° C.overnight. Methanol (2 ml) was added to the reaction mixture, and afterstirring for 10 minutes, the reaction mixture was passed through SCX(Bond Elute SCX500MG) and the SCX was washed with methanol. Afterelution with a 2N ammonia-methanol solution, the solvent was distilledoff under reduced pressure to obtain a residue. The residue was purifiedby preparative HPLC to obtain2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylicacid isopropylamide. The compound was identified by LC-MS.

Yield: 25.6 mg (78.1%), Purity: 97.3%, [M+1]=490.1

Example 1-4-19 to Example 1-4-30

Compound Nos. 1-4-19 to 1-4-30 were synthesized in the same manner asExample 1-4-18, using the corresponding starting materials. The resultsare shown in Table 12. TABLE 12 Compound No. 1-4- Yield (mg) Yield (%)MW M + 1 1 10 39 463.4 463.1 2 19 80 428.9 429.1 3 28 100 473.4 473.1 418 74 439.5 440.1 5 26 100 428.5 429.2 6 28 100 431.5 432.2 7 28 100434.6 435.1 8 24 98 406.5 407.2 9 294 44 447.4 447.1 10 9 41 472.0 472.211 11 42 516.4 518.1(Br) 12 17 74 482.5 483.2 13 12 49 506.4 506.1 14 627 471.6 472.2 15 10 43 474.6 475.2 16 14 59 477.6 478.2 17 22 96 449.6450.2 18 26 78 490.4 490.1 19 18 56 476.4 476.1 20 24 68 520.5 520.2 2123 66 518.4 518.1 22 4 22 517.5 517.3 23 9 51 503.5 503.3 24 13 67 575.5575.3 25 2 12 518.4 518.3 26 21 116 518.4 518.3 27 11 62 490.4 490.2 2811 61 522.5 522.3 29 13 69 536.5 536.3 30 7 84 475.4 475.2

Reference Example 1-5-1 Synthesis of 3,4-diaminobenzoic acid ethyl ester

3,4-Diaminobenzoic acid (2.003 g, 13.17 mmol) and triphenylphosphine(4.248 g, 16.20 mmol) were suspended in toluene (20 ml) andtetrahydrofuran (10 ml). Ethanol (2 ml) was then added, diisopropylazodicarboxylate (2.5 ml, 9.96 mmol) was added dropwise to the obtainedlight brown suspension, and the mixture was stirred at room temperaturefor 3.5 hours. Isopropyl azodicarboxylate (1.5 ml, 5.98 mmol) wasfurther added dropwise, the mixture was stirred at room temperature for1 hour, and the obtained reaction mixture was extracted with 1Nhydrochloric acid (100 ml×2 times), after which the aqueous layer waswashed with 50 ml of ethyl acetate. After adding 2N aqueous sodiumhydroxide to the aqueous layer to raise the pH to 11 or higher, theprecipitate was extracted with ethyl acetate (100 ml×2 times). Theorganic layer was washed with saturated brine (50 ml) and driedovernight over anhydrous sodium sulfate. The desiccant was filtered outand the filtrate was concentrated to obtain 3,4-diaminobenzoic acidethyl ester as a faint yellow solid. The compound was identified byLC-MS.

Yield: 1.547 g (65%), Found: ESI/MS m/e 181.1(M+1).

The following compounds were also synthesized in the same manner asReference Example 1-5-1, using the corresponding starting materials.

-   3,4-Diaminobenzoic acid isopropyl ester: Yield=1.302 g (49%)-   3,4-Diaminobenzoic acid isobutyl ester: Yield=2.014 g (72%)-   3,4-Diaminobenzoic acid benzyl ester: Yield=0.331 g (10%)-   3,4-Diaminobenzoic acid cyclohexyl ester: Yield=0.245 g (8%)

Reference Example 1-5-2 Synthesis of2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylicacid ethyl ester

4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.394 g,1.84 mmol) was dissolved in acetonitrile (3 ml). A solution ofthiocarbonyldiimidazole (0.340 g, 1.91 mmol) and imidazole (0.052 g,0.77 mmol) in acetonitrile (6 ml) was added dropwise over 3 minutes, at0° C. The mixture was stirred at room temperature for 1 hour,3,4-diaminobenzoic acid ethyl ester (0.371 g, 2.06 mmol) was added tothe reaction mixture, and the mixture was stirred at 50° C. for 5.5hours. Diisopropylcarbodiimide (0.32 ml) was further added, and themixture was stirred overnight at 50° C. Saturated brine was then addedto the obtained reaction mixture, extraction was performed with ethylacetate (100 ml), and the organic layer was dried overnight overanhydrous sodium sulfate. After filtering out the desiccant andconcentrating the filtrate, the obtained light brown oil was purified bysilica gel column chromatography (dichloromethane/methanol=49/1 →19/1)to obtain2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylicacid ethyl ester as a yellow amorphous solid.

Yield: 0.838 g (%), Found: ESI/MS m/e 403.2(M+1).

Reference Example 1-5-3 Synthesis of2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylic acidethyl ester

After dissolving the2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylicacid ethyl ester in tetrahydrofuran (2 ml), a 4N hydrogenchloride/1,4-dioxane solution (3 ml) was added. Since a precipitate wasproduced, ethanol (5 ml) was added to dissolve it and the solution wasstirred at room temperature overnight. The reaction mixture wasconcentrated to obtain2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylic acidethyl ester as a red amorphous solid. The compound was identified byLC-MS.

Yield: 0.942 g (100%), Found: ESI/MS m/e 303.1(M+1).

Example 1-5-1 Synthesis of2-{[1-(3,5-dichloro-2-hydroxybenzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-5-carboxylicacid ethyl ester

After adding 3,5-dichloro-2-hydroxybenzaldehyde (0.3 mmol) and sodiumtriacetoxyborohydride (0.3 mmol) to a solution of2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylic acidethyl ester (0.1 mmol) in dimethylformamide-acetic acid (10:1) (1.0 ml),the mixture was stirred at room temperature overnight. Methanol (1.0 ml)was added to the reaction mixture to suspend the reaction, and afterstirring for 1 hour, the solution was passed through SCX (Bond EluteSCX500MG). The SCX was washed with methanol and then with a mixedsolution of chloroform/methanol (1/1), and elution was performed with a0.5N ammonia-dioxane solution. The solvent was distilled off underreduced pressure, and the obtained residue was subjected to preparativeHPLC to obtain2-{[1-(3,5-dichloro-2-hydroxybenzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-5-carboxylicacid ethyl ester. The compound was identified by LC-MS.

Yield: 1.6 mg (3.4%), Purity: 98%, Found: ESI/MS m/e 477.1(M+1).

Example 1-5-2 to Example 1-5-8

Compound Nos. 1-5-2 to 1-5-8 were synthesized in the same manner asReference Examples 1-5-1 to 1-5-3 and Example 1-5-1, using thecorresponding starting materials. The results are shown in Table 13.

Reference Example 1-5-4 Synthesis of 3,4-diaminobenzoic acid methylester

Thionyl chloride (13.0 ml, 180 mmol) was slowly added dropwise at 0° C.to a solution of 3,4-diaminobenzoic acid (25.0 g, 164 mmol) in methanol(164 ml). After stirring the mixture at room temperature overnight, itwas further stirred at 80° C. overnight. The reaction mixture was cooledto room temperature, and the precipitated solid was filtered out andwashed with methanol. The filtrate was concentrated under reducedpressure and the obtained solid was filtered out and washed withmethanol. All of the obtained solid was dried under reduced pressure at60° C. to obtain 3,4-diaminobenzoic acid methyl ester. The compound wasidentified by NMR.

Yield: 31.16 g (79%).

¹H-NMR (270 MHz, CDCl₃): 3.76(s, 3H), 6.85(d, 1H, J=8.6 Hz), 7.63(dd,1H, J=1.9, 8.6 Hz), 7.78(d, 1H, J=1.9 Hz).

Example 1-5-9 to Example 1-5-13

Compound Nos. 1-5-9 to 1-5-13 were synthesized in the same manner asReference Example 1-5-4, Reference Example 1-5-2, Reference Example1-5-3 and Example 1-5-1, using the corresponding starting materials. Theresults are shown in Table 13.

Reference Example 1-5-5 Synthesis of 4-methylamino-3-nitrobenzoic acidmethyl ester

After dissolving 4-fluoro-3-nitrobenzoic acid methyl ester (507.3 mg,2.55 mmol) in tetrahydrofuran (1 ml), methylamine (2.0 M tetrahydrofuransolution, 2.55 ml, 5.09 mmol) was added in an ice bath, and the mixturewas stirred at room temperature overnight; The reaction mixture wasconcentrated under reduced pressure and dissolved in ethyl acetate (20ml), and after washing in saturated aqueous sodium bicarbonate andbrine, it was dried over anhydrous magnesium sulfate. It was thenconcentrated under reduced pressure, the obtained residue was dissolvedin a methylamine-tetrahydrofuran solution (2.0 M, 3 ml), and uponsealing, the solution was stirred at 50° C. for 5 hours. The reactionmixture was concentrated under reduced pressure and dissolved in ethylacetate (30 ml), and the solution was washed with saturated aqueoussodium bicarbonate and brine and then dried over anhydrous magnesiumsulfate. The dried product was concentrated under reduced pressure toobtain 4-methylamino-3-nitro-benzoic acid methyl ester. The compound wasidentified by LC-MS.

Yield: 540 mg (100%), [M+1]=211.1.

Reference Example 1-5-6 Synthesis of 3-amino-4-methylaminobenzoic acidmethyl ester

After dissolving 4-methylamino-3-nitrobenzoic acid methyl ester (540 mg,2.5 mmol) in ethyl acetate-methanol (2:1) (20 ml), 10% palladium-carbonpowder (5 mol %) was added thereto under a nitrogen atmosphere. Themixture was stirred for 4 hours under a hydrogen atmosphere, and thenthe reaction mixture was filtered through celite. The filtrate wasconcentrated under reduced pressure to obtain3-amino-4-methylaminobenzoic acid methyl ester. The compound wasidentified by LC-MS.

Yield: 441 mg (100%), [M+1]=181.1.

Example 1-5-14 to Example 1-5-16

Compound Nos. 1-5-14 to 1-5-16 were synthesized in the same manner asReference Example 1-5-5, Reference Example 1-5-6, Reference Example1-5-2, Reference Example 1-5-3 and Example 1-5-1, using thecorresponding starting materials. The results are shown in Table 13.

Reference Example 1-5-7 Synthesis of4-tert-butoxycarbonylamino-3-nitrobenzoic acid methyl ester

After dissolving 4-amino-3-nitrobenzoic acid methyl ester (1.03 g, 5.25mmol) in tetrahydrofuran (50 ml), sodium bis(trimethylsilyl)amide (1.0 Mtetrahydrofuran solution, 10.5 ml, 10.5 mmol) was added and the mixturewas stirred at room temperature for 15 minutes. A solution of dibutyldicarbonate (1.44 ml, 6.30 mmol) in tetrahydrofuran (10 ml) was addeddropwise thereto, and the mixture was stirred at room temperature for 1hour. The reaction mixture was concentrated under reduced pressure, and1N hydrochloric acid was added to the residue to adjust the pH toapproximately 6. The mixture was then extracted with ethyl acetate (100ml×3 times), and the obtained organic layer was washed with saturatedbrine and then dried over anhydrous magnesium sulfate. The residueobtained by concentration under reduced pressure was purified by silicagel column chromatography (n-hexane/ethyl acetate=9/1) to obtain4-tert-butoxycarbonylamino-3-nitrobenzoic acid methyl ester. Thecompound was identified by LC-MS.

Yield: 1.11 g (71.4%), [M+1]=297.1.

Reference Example 1-5-8 Synthesis of3-amino-4-tert-butoxycarbonylaminobenzoic acid methyl ester

4-tert-Butoxycarbonylamino-3-nitrobenzoic acid methyl ester (1.11 g,3.75 mmol) was dissolved in ethyl acetate-methanol (1:1) (30 ml). Next,10% palladium-carbon powder (200 mg, 5 mol %) was added to the aqueoussolution under a nitrogen atmosphere, and the mixture was stirredovernight under a hydrogen atmosphere. The reaction mixture was filteredwith celite, and the filtrate was concentrated under reduced pressure toobtain 3-amino-4-tert-butoxycarbonylaminobenzoic acid methyl ester. Thecompound was identified by LC-MS.

Yield: 924.1 mg (92.3%), [M+1]=267.3.

Reference Example 1-5-9 Synthesis of4-tert-butoxycarbonylamino-3-(2-nitro-benzenesulfonylamino)-benzoic acidmethyl ester

After dissolving 3-amino-4-tert-butoxycarbonylaminobenzoic acid methylester (817.3 mg, 3.07 mmol) in dichloromethane (10 ml), pyridine (0.373ml, 4.60 mmol) and 2-nitrobenzenesulfonyl chloride (815 mg, 3.68 mmol)were added in an ice bath, and the mixture was stirred at roomtemperature for 4 hours. Pyridine (0.050 ml) and 2-nitrobenzenesulfonylchloride (135 mg) were added, and stirring was continued for 2 hours.The reaction mixture was concentrated under reduced pressure, water (30ml) was added, and then extraction was performed with ethyl acetate (20ml×3 times). The obtained organic layer was washed with saturated brineand then dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the crystallized residue was suspended inn-hexane-ethyl acetate (4:1), filtered, and dried to obtain4-tert-butoxycarbonylamino-3-(2-nitro-benzenesulfonylamino)-benzoic acidmethyl ester. The compound was identified by LC-MS.

Yield: 1.23 g (88.7%).

Reference Example 1-5-10 Synthesis of4-tert-butoxycarbonylamino-3-[methyl-(2-nitro-benzenesulfonyl)-amino]-benzoicacid methyl ester

After dissolving4-tert-butoxycarbonylamino-3-(2-nitro-benzenesulfonylamino)-benzoic acidmethyl ester (1.23 g, 2.73 mmol) in dimethylformamide (10 ml), potassiumcarbonate (1.13 g, 8.16 mmol) and methyl iodide (0.254 ml, 4.09 mmol)were added in an ice bath, and the mixture was stirred at roomtemperature for 2 hours. Water (100 ml) was added to the reactionmixture, and extraction was performed with ethyl acetate (40 ml×4times). The obtained organic layer was washed with saturated brine andthen dried over anhydrous magnesium sulfate. After concentration underreduced pressure, the crystallized residue was dried to obtain4-tert-butoxycarbonylamino-3-[methyl-(2-nitro-benzenesulfonyl)-amino]-benzoicacid methyl ester. The compound was identified by LC-MS.

Yield: 1.41 g (100%).

Reference Example 1-5-11 Synthesis of4-tert-butoxycarbonylamino-3-methylamino-benzoic acid methyl ester

After dissolving4-tert-butoxycarbonylamino-3-[methyl-(2-nitro-benzenesulfonyl)-amino]-benzoicacid methyl ester (1.41 g, 2.73 mmol) in dimethylformamide (10 ml),potassium carbonate (1.13 g, 8.16 mmol) and thiophenol (0.307 ml, 2.99mmol) were added in an ice bath, and the mixture was stirred at roomtemperature for 1 hour. Water (100 ml) was added to the reactionmixture, and extraction was performed with ethyl acetate (40 ml×3times). The obtained organic layer was washed with saturated brine andthen dried over anhydrous magnesium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography (n-hexane/ethyl acetate=85/15) to obtain4-tert-butoxycarbonylamino-3-methylamino-benzoic acid methyl ester. Thecompound was identified by LC-MS. Yield: 794.3 mg (62.7%), [M+1]=281.1.

Reference Example 1-5-12 Synthesis of 4-amino-3-methylaminobenzoic acidmethyl ester

After dissolving 4-tert-butoxycarbonylamino-3-methylaminobenzoic acidmethyl ester (794.3 mg, 2.83 mmol) in methanol (7.0 ml), a 4N hydrogenchloride-1,4-dioxane solution (3.54 ml, 14.3 mmol) was added in an icebath, and the mixture was stirred at room temperature for 30 minutes. Anequivalent amount of the 4N hydrogen chloride-1,4-dioxane solution wasfurther added, and the mixture was stirred at 40° C. for 30 minutes. Thereaction mixture was poured into ice-cooled saturated aqueous sodiumbicarbonate, and was extracted with ethyl acetate (30 ml×3). Theobtained organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The residue obtained by concentration underreduced pressure was purified by silica gel column chromatography(n-hexane/ethyl acetate=4/1→3/2→1/1) to obtain4-amino-3-methylaminobenzoic acid methyl ester. The compound wasidentified by LC-MS.

Yield: 342.7 mg (67.2%), [M+1]=181.1.

Example 1-5-17 to Example 1-5-19

Compound Nos. 1-5-17 to 1-5-19 were synthesized in the same manner asReference Examples 1-5-7 to 1-5-12, Reference Example 1-5-2, ReferenceExample 1-5-3 and Example 1-5-1, using the corresponding startingmaterials. The results are shown in Table 13.

Example 1-5-20 Synthesis of2-{[1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-5-carboxylicacid

After suspending2-{[1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-5-carboxylicacid methyl ester (3.2 mmol) in methanol (10 ml), a 4N lithium hydroxideaqueous solution (5.4 ml, 21.4 mmol) was added. The reaction mixture wasstirred at 50° C. for 2 hours and then cooled to room temperature. Next,1N hydrochloric acid was added dropwise to adjust the pH toapproximately 6.0. Ethyl acetate (1 ml) was added to the aqueoussolution and the mixture was stirred for 3 hours, and then theprecipitate was filtered out to obtain2-{[1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-5-carboxylicacid. The compound was identified by LC-MS.

Yield: 1.01 g (79.9%), Purity: 98.5%, [M+1]=393.1.

Example 1-5-21 to Example 1-5-22

Compound Nos. 1-5-21 to 1-5-22 were synthesized in the same manner asExample 1-5-20, using the corresponding starting materials. The resultsare shown in Table 13.

Example 1-5-23 Synthesis of2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylicacid (2-dimethyl)-amide

2-[(1-Naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylicacid (20.0 mg, 0.0480 mmol) and 1-hydroxybenzotriazole monohydrate (22.0mg, 0.145 mmol) were dissolved in tetrahydrofuran-dimethylformamide(1:1, 0.500 ml). After then adding N,N-dimethylethylenediamine (0.0160ml, 0.145 mmol) and N,N-diisopropylcarbodiimide (0.0220 ml, 0.145 mmol)thereto, the mixture was stirred at room temperature overnight. Water (2ml) was added to the reaction mixture, and after stirring for 10minutes, extraction was performed with ethyl acetate (1 ml×3 times). Theobtained ethyl acetate layer was purified by SCX solid phase extractionand then purified by preparative HPLC to obtain2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylicacid (2-dimethyl)-amide. The compound was identified by LC-MS.

Yield: 10.5 mg (45.1%), Purity: 100%, [M+1]=485.4

Example 1-5-24 to Example 1-5-190

Compound Nos. 1-5-24 to 1-5-190 were synthesized in the same manner asExample 1-5-23, using the corresponding starting materials. The resultsare shown in Table 13.

Reference Example 1-5-13 Synthesis of2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-benzimidazole-1,5-dicarboxylicacid 1-tert-butyl ester 5-methyl ester

After dissolving2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylicacid methyl ester (1 g, 2.33 mmol) in 1,4-dioxane (25 ml), di-t-butyldicarbonate (1017 mg, 4.66 mmol) was added and the mixture was stirredat 80° C. for 11 hours. The solvent was distilled off under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (dichloromethane/methanol/TEA=85/10/5) to obtain2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-benzimidazole-1,5-dicarboxylicacid 1-tert-butyl ester 5-methyl ester. The compound was identified byLC-MS.

Yield: 1.1 g (96%), LC-MS (529.2 m/z M+1).

Example 1-5-191 Synthesis of{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-5-yl}-methanol

After dissolving2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-benzimidazole-1,5-dicarboxylicacid 1-tert-butyl ester 5-methyl ester (940 mg, 1.78 mmol) in drytetrahydrofuran (18 ml) under a nitrogen stream, aluminum lithiumhydride (135 mg, 3.56 mmol) was added at 0° C., and the mixture wasstirred for 3 hours. Saturated aqueous sodium sulfate was added, andthen the solvent was distilled off under reduced pressure. Since theresidue contained water, it was dissolved in ethyl acetate and washedwith saturated brine, and the solvent was then distilled off underreduced pressure to obtain a residue. The residue was purified by silicagel column chromatography (dichloromethane/methanol/TEA=90/5/5) toobtain{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-5-yl-}-methanol.

Yield: 822 mg (91%), Purity: 89.3%, LC-MS (401.2 m/z M+1).

Example 1-5-192 Synthesis of2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboaldehyde

A solution of 1-hydroxy-1-oxo-1H-1λ⁵-benzo[d][1,2]iodoxol-3-one (846 mg,3.02 mmol) in dimethylsulfoxide (10 ml) was added to a solution of{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-5-yl}-methanol(807 mg, 2.01 mmol) in dimethylsulfoxide (10 ml), and the mixture wasstirred at room temperature for 9 hours. The reaction mixture was pouredinto ice water (200 ml) and stirred at room temperature for 30 minutes,after which ethyl acetate was added and stirring was continuedvigorously for 10 minutes for extraction. After washing with saturatedaqueous sodium bicarbonate and saturated brine, the mixture was driedover anhydrous sodium sulfate, the solvent was distilled off underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (ethyl acetate/methanol=9/1). This was furtherpurified by preparative HPLC to obtain2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboaldehyde.

Yield: 34 mg (4%), Purity: 100%, LC-MS (399.2 m/z M+1).

Example 1-5-193 Synthesis of2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carbonitrile

After dissolving2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboaldehyde(2.7 mg, 0.0570 mmol) in anhydrous dimethylformamide (1 ml) under anitrogen stream, hydroxylamine hydrochloride (8 mg, 0.115 mmol) and onedrop of 6N hydrochloric acid were added and the mixture was stirred at80° C. for 2 hours and 30 minutes. Two drops of 5N aqueous sodiumhydroxide were then added, and after extraction with ethyl acetate,extraction was repeated with dichloromethane. The organic layer waswashed with saturated brine and then dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure toobtain a residue. Anhydrous dimethylformamide (1 ml) and nine drops of a4N hydrogen chloride/1,4-dioxane solution were added to the residue, andthe mixture was stirred at 100° C. for 12 hours. After neutralizationwith 5N aqueous sodium hydroxide, the same extraction procedure wascarried out and the obtained residue was purified by thin-layer silicagel chromatography (dichloromethane/methanol/triethylamine=85/10/5) toobtain2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carbonitrile.

Yield: 29%, Purity: 99.3%, Yield: 6.6 mg. LC-MS (396.3 m/z M+1).

Reference Example 1-5-14 Synthesis of2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-5-carboxylicacid methyl ester

After dissolving2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylicacid methyl ester (1 g, 2.33 mmol) in anhydrous tetrahydrofuran (30 ml)under a nitrogen stream, the mixture was cooled to 0° C. Next, 60%sodium hydride (187 mg, 4.89 mmol) was added and the mixture was stirredat 0° C. for 72 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (815.8mg, 4.89 mmol) was further added, the mixture was stirred at 0° C. for30 minutes, and then water was added. The solution was extracted withethyl acetate and then with dichloromethane, and each extract was washedwith saturated brine and then combined and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theobtained residue was purified by silica gel column chromatography (ethylacetate/hexane=2/3→3/2→1/0) to obtain2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-5-carboxylicacid methyl ester. The compound was identified by LC-MS.

Yield: 624 mg (39%), Purity: 95.1%, LC-MS (689.3 m/z M+1).

Reference Example 1-5-15 Synthesis of[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-methanol

After dissolving2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-5-carboxylicacid methyl ester (624 mg, 0.91 mmol) in anhydrous tetrahydrofuran (10ml) under a nitrogen stream, aluminum lithium hydride (72.4 mg, 1.82mmol) was added at 0° C., and the mixture was stirred for 2 hours. Afterthen adding a saturated aqueous sodium sulfate solution, extraction wasperformed with ethyl acetate and then with dichloromethane. Each extractwas washed with saturated brine, and then combined and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure to obtain[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-methanol.The compound was identified by LC-MS.

Yield: 568 mg (95%), Purity: 89.4%, LC-MS (661.4 m/z M+1).

Reference Example 1-5-16 Synthesis of2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-5-carboaldehyde

A solution of[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-methanol(467 mg, 0.71 mmol) in dimethylsulfoxide (5 ml) was added to a solutionof 297 mg of 1-hydroxy-1-oxo-1H-1λ⁵-benzo[d][1,2]iodoxol-3-one (1.06mmol) in dimethylsulfoxide (5 ml), and the mixture was stirred at roomtemperature for 18 hours. The reaction mixture was poured into ice water(200 ml) and stirred at room temperature for 30 minutes, after whichethyl acetate was added and stirring was continued vigorously for 10minutes for extraction. After washing with saturated aqueous sodiumbicarbonate and then with saturated brine, the mixture was dried overanhydrous sodium sulfate, and then the solvent was distilled off underreduced pressure to obtain2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-5-carboaldehyde.

Yield: 475 mg (100%), Purity: 83.2%, LC-MS (659.3 m/z M+1).

Reference Example 1-5-17 Synthesis of1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-ol

After dissolving2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-5-carboaldehyde(86 mg, 0.131 mmol) in anhydrous tetrahydrofuran (1.2 ml) under anitrogen stream, ethylmagnesium bromide (0.26 ml, 1M tetrahydrofuransolution) was added at 0° C., and the mixture was stirred at roomtemperature for 13 minutes. Saturated aqueous ammonium chloride wasadded, and extraction was performed with ethyl acetate. The organiclayer was washed with saturated brine and then dried over sodiumsulfate, and the solvent was distilled off under reduced pressure toobtain1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-ol.

Yield: 92.5 mg (100%), Purity: 88%, LC-MS (689.3 m/z M+1).

Example 1-5-194 Synthesis of1-{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-5-yl}-propan-1-ol

After dissolving1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-ol(50 mg, 0.073 mmol) in anhydrous dimethylformamide (2 ml),tetrabutylammonium fluoride (0.5 ml, 1.0 M tetrahydrofuran solution) wasadded and the mixture was stirred at 100° C. for 13 hours. Ethyl acetateand water were added, after which the aqueous layer was adjusted to pH11 and extracted with ethyl acetate. The organic layer was washed withsaturated brine and then dried over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure, and the obtainedresidue was purified by thin-layer silica gel chromatography (ethylacetate/methanol=4/1). The purified product was further purified bypreparative HPLC to obtain1-{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-5-yl}-propan-1-ol.

Yield: 1.08 mg (3%), Purity: 100%, LC-MS (429.2 m/z M+1).

Reference Example 1-5-18 Synthesis of1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-[(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-one

A solution of1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-ol(72 mg, 0.10 mmol) in dimethylsulfoxide (1 ml) was added to a solutionof 1-hydroxy-1-oxo-1H-1λ⁵-benzo[d][1,2]iodoxol-3-one (44 mg, 0.157 mmol)in dimethylsulfoxide (1 ml), and the mixture was stirred at roomtemperature for 18 hours. The reaction mixture was poured into ice water(50 ml) and stirred at room temperature for 30 minutes, after whichethyl acetate was added and stirring was continued vigorously for 10minutes for extraction. After washing with saturated aqueous sodiumbicarbonate and then with saturated brine, the mixture was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure to obtain1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-one.

Yield: 64 mg (89%), Purity: 92.8%, LC-MS (687.4 m/z M+1)

Example 1-5-195 Synthesis of1-{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-5-yl}-propan-1-one

After dissolving1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-one(32 mg, 0.047 mmol) in anhydrous dimethylformamide (1 ml),tetrabutylammonium fluoride (0.8 ml, 1.0 M tetrahydrofuran solution) andwater (5 μl) were added, and the mixture was stirred at 100° C. for 2hours and 30 minutes. Water and ethyl acetate were added, and extractionwas performed with ethyl acetate. The organic layer was washed withsaturated brine and then dried over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure, and the obtainedresidue was purified by thin-layer silica gel chromatography(dichloromethane/methanol/TEA=85/10/1). The purified product was furtherpurified by preparative HPLC and thin-layer silica gel chromatography(dichloromethane/methanol=8/2) to obtain1-{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-5-yl}-propan-1-one.

Yield: 2.04 mg (10%), Purity: 100%, LC-MS (427.2 m/z M+1).

Example 1-5-196 and Example 1-5-197

Compound Nos. 1-5-196 and 1-5-197 were synthesized in the same manner asExample 1-5-195, using the corresponding starting materials. The resultsare shown in Table 13. TABLE 13 Compound No. 1-5- Yield (mg) Yield (%)MW M + 1 1 2 3 477.4 477.1 2 14 31 442.9 443.1 3 15 35 442.6 443.2 4 1229 420.6 421.2 5 1 2 491.4 491.2 6 4 9 457.0 457.2 7 11 26 456.6 457.2 821 52 434.6 435.2 9 48 92 428.5 429.1 10 51 100 406.5 407.2 11 8 20463.4 463.1 12 13 36 439.5 440.1 13 500 58 434.6 435.1 14 19 28 477.4477.1 15 41 100 442.6 443.2 16 45 100 420.6 421.2 17 6 24 477.4 477.1 1823 99 442.6 443.2 19 24 100 420.6 421.2 20 1010 80 392.5 393.1 21 994 93417.5 418.1 22 458 67 459.3 459.4 23 11 45 484.6 485.4 24 10 43 498.6499.4 25 39 100 556.7 557.5 26 13 53 499.6 500.3 27 13 57 471.6 472.3 2812 51 503.6 504.4 29 4 16 517.7 518.4 30 17 51 455.6 456.4 31 12 35469.6 470.3 32 8 23 483.7 484.4 33 3 10 469.6 470.4 34 7 18 499.6 500.435 17 52 457.6 458.4 36 15 43 471.6 472.3 37 6 19 456.6 457.4 38 25 100433.6 434.2 39 10 43 462.6 463.2 40 4 16 476.6 477.2 41 7 27 534.7 535.342 9 36 477.6 478.2 43 8 36 435.6 436.2 44 29 100 477.6 478.2 45 27 100449.6 450.2 46 29 100 481.6 482.3 47 29 100 495.7 496.3 48 14 61 458.6459.2 49 9 39 487.7 488.3 50 11 47 502.6 503.3 51 10 42 474.6 475.2 52 939 506.7 507.2 53 10 38 520.7 521.3 54 11 24 456.0 456.2 55 13 27 485.0485.2 56 8 16 499.0 499.2 57 9 16 557.1 557.2 58 16 32 500.0 500.1 59 1020 500.0 500.2 60 15 32 472.0 472.2 61 17 34 504.0 504.1 62 19 37 518.1518.2 63 21 48 440.0 440.2 64 8 17 469.0 469.1 65 23 48 483.0 483.2 6619 35 541.1 541.2 67 9 19 484.0 484.2 68 2 5 442.0 442.1 69 11 23 484.0484.1 70 26 53 488.0 488.2 71 29 58 502.1 502.2 72 21 46 456.0 456.1 7314 31 457.6 458.2 74 15 34 435.6 436.2 75 5 11 460.6 461.2 76 14 31458.0 458.1 77 11 25 442.0 442.1 78 14 32 441.6 442.2 79 12 29 419.6420.2 80 10 22 444.6 445.2 81 15 34 442.0 442.2 82 10 23 426.0 426.1 839 21 427.5 428.2 84 10 25 405.5 406.2 85 2 5 430.6 431.2 86 10 23 427.9428.1 87 23 56 411.9 412.2 88 12 45 522.5 522.0 89 13 52 518.4 518.1 906 29 474.4 474.0 91 11 47 503.5 503.1 92 10 41 517.5 517.1 93 6 26 518.4518.1 94 5 20 490.4 490.0 95 11 42 575.5 575.1 96 9 37 536.5 536.0 97 1860 475.4 475.2 98 24 92 490.4 490.0 99 12 28 476.4 476.0 100 8 15 557.5557.3 101 5 10 543.5 543.3 102 5 9 526.5 526.3 103 5 8 538.5 538.1 104 510 516.5 516.3 105 5 10 542.6 542.3 106 8 16 514.4 514.2 107 2 5 486.4486.2 108 4 9 478.4 484.3 109 4 7 544.5 544.2 110 11 20 546.5 546.3 1113 5 560.5 560.3 112 10 20 517.5 517.2 113 12 22 530.5 531.3 114 10 21471.4 471.1 115 3 5 532.5 532.3 116 7 14 472.4 473.3 117 10 18 516.5516.3 118 9 18 502.5 502.0 119 7 14 543.5 543.3 120 3 6 486.4 486.3 1214 8 502.5 502.3 122 10 19 528.5 528.2 123 7 14 502.5 502.0 124 9 18488.5 488.2 125 7 13 570.6 570.2 126 33 70 472.4 473.3 127 20 38 542.6543.3 128 33 60 545.6 545.3 129 24 47 516.5 517.3 130 31 56 545.6 545.4131 28 55 502.5 503.3 132 32 70 460.4 461.2 133 23 45 518.5 519.3 134 2548 530.5 531.3 135 23 45 502.5 503.3 136 23 44 518.5 519.3 137 19 37520.5 521.3 138 16 30 528.5 529.3 139 19 36 528.5 529.3 140 33 70 470.4471.3 141 19 34 556.6 557.4 142 15 30 517.5 517.3 143 17 34 488.5 489.3144 20 41 488.5 489.3 145 20 41 488.5 489.3 146 7 14 516.5 517.3 147 2241 531.5 529.3 148 17 30 559.5 559.3 149 16 34 474.4 475.2 150 21 41500.5 501.3 151 15 29 514.5 515.3 152 9 18 504.5 505.3 153 34 58 573.6573.4 154 28 56 504.5 504.3 155 35 61 571.6 571.4 156 31 59 529.5 529.3157 28 48 587.6 587.4 158 20 36 546.5 547.3 159 3 6 500.5 500.2 160 2 3502.4 502.3 161 2 4 528.5 528.2 162 1 2 516.5 516.3 163 1 2 532.5 532.3164 2 4 517.5 517.3 165 36 71 503.4 503.3 166 19 38 489.4 489.2 167 6 10550.5 550.3 168 3 6 503.4 503.3 169 2 4 485.4 485.2 170 1 2 502.5 502.1171 2 3 508.9 508.1 172 4 6 559.6 559.3 173 3 6 502.5 502.0 174 22 37589.6 589.4 175 21 35 603.6 603.3 176 5 10 523.5 523.2 177 6 12 523.5523.2 178 5 10 523.5 523.2 179 5 11 504.5 504.3 180 7 14 508.5 508.2 1812 3 520.9 520.2 182 2 3 488.5 488.2 183 4 7 538.5 538.1 184 821 100400.5 401.2 185 34 4 398.5 399.2 186 7 29 395.5 396.3 187 1 3 428.6429.2 188 2 9 426.6 427.2 189 4 1 412.5 413.2 190 3 1 440.6 441.2 191822 91 400.5 401.2 192 34 4 398.6 399.2 193 7 29 395.6 396.3 194 1 3428.5 429.2 195 2 10 426.6 427.2 196 7 18 499.0 500.4 197 871 41 428.0429.2

Example 1-6-1 Synthesis of[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-(1-ethyl-1H-benzimidazol-2-yl)-amine

After dissolving(1H-benzimidazol-2-yl)-[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amine(20 mg, 0.05 mmol) in dimethylformamide (1 ml), ethyl bromide (0.075mmol) and sodium hydride (0.1 mmol) were added, and the mixture wasstirred at room temperature for 3 hours and 30 minutes. Ice and dilutedhydrochloric acid were added to the reaction mixture to suspend thereaction, and the solution was passed through SCX (Bond Elute SCX500MG).The SCX was washed with methanol and elution was performed with a 2Nammonia-methanol solution, after which the obtained eluate was distilledoff under reduced pressure. The residue was purified by thin-layersilica gel chromatography (hexane/ethylacetate/dichloromethane/methanol=60/25/10/5) to obtain[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-(1-ethyl-1H-benzimidazol-2-yl)-amineand[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-ethyl-(1-ethyl-1H-benzimidazol-2-yl)-amine.The compounds were identified by LC-MS.

Yield: 5.8 mg (28%), Purity: 100%, Found: ESI/MS m/e 417.0 (M+1).

Example 1-6-2

Compound No. 1-6-2,[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-ethyl-(1-ethyl-1H-benzimidazol-2-yl)-amine,was synthesized in the same manner as Example 1-6-1, using thecorresponding starting materials.

Yield: 7.7 mg (35%), Purity: 100%, Found: ESI/MS m/e 445.1 (M+1).

Example 1-6-3 to Example 1-6-15

Compound Nos. 1-6-3 to 1-6-15 were synthesized in the same manner asExample 1-6-1, using the corresponding starting materials. The resultsare shown in Table 14. TABLE 14 Compound No. 1-6- Yield (mg) Yield (%)MW M + 1 1 6 28 417.4 417.0 2 8 35 445.4 445.1 3 15 52 569.6 569.3 4 623 479.5 479.3 5 6 20 557.6 557.2 6 6 26 473.5 473.1 7 1 3 625.7 625.4 89 34 507.5 507.3 9 2 7 461.4 461.2 10 6 24 517.5 517.2 11 3 13 446.4446.2 12 3 15 460.4 460.1 13 8 33 461.4 461.2 14 4 20 442.4 443.1 15 624 489.4 489.2

Synthesis of Quinazolinone Derivatives (1) Reference Example 2-1Synthesis of {1-[(3,4-dichlorophenyl)methyl]-4-piperidyl}methylamine

After dissolving 4-aminomethylpiperidine (13.7 g, 120 mmol) inacetonitrile (200 ml), potassium carbonate (11.057 g, 80 mmol) and3,4-dichlorobenzyl chloride (7.818 g, 40 mmol) were added and themixture was stirred at 60° C. overnight. After completion of thereaction, the reaction mixture was filtered and the solvent wasdistilled off. Purification was performed by silica gel columnchromatography (dichloromethane/methanol/triethylamine=90/5/5) to obtain{1-[(3,4-dichlorophenyl)methyl]-4-piperidyl}methylamine. The compoundwas identified by LC-MS.

Yield: 10.8 g (quantitative, M+1=273.1.

Reference Example 2-2 Synthesis ofN-{[({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)amino]thioxomethyl}(fluoren-9-ylmethoxy)carboxamide

After dissolving {1-[(3,4-dichlorophenyl)methyl]-4-piperidyl}methylamine(1325 mg, 4.84 mmol) in tetrahydrofuran (20 ml), FmocNCS(9-fluorenylmethoxycarbonyl isothiocyanate) (1498 mg, 5.32 mmol) wasadded, and the mixture was stirred at room temperature overnight. Aftercompletion of the reaction, the reaction mixture was concentrated andpurified by silica gel column chromatography (hexane/ethylacetate=85/15) to obtainN-{[({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)amino]thioxomethyl}(fluoren-9-ylmethoxy)carboxamide.The compound was identified by LC-MS.

Yield: 2624 mg (98%), M+1=554.1.

Reference Example 2-3 Synthesis ofamino[({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)amino]methane-1-thione

After dissolvingN-{[({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)amino]thioxomethyl}(fluoren-9-ylmethoxy)carboxamide(553 mg, 1 mmol) in DMF (4 ml), piperidine (0.989 ml, 10 mmol) was addedand the mixture was stirred at room temperature overnight. Uponcompletion of the reaction, water (20 ml) was added and extraction wasperformed with ethyl acetate (20 ml×3 times). The extracted organiclayer was washed with water (100 ml×2 times) and then with saturatedbrine, dried over anhydrous sodium sulfate, and then filtered andconcentrated. Purification was performed by silica gel columnchromatography (ethyl acetate/methanol=1/0→4/1) to obtainamino[({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)amino]methane-1-thione.The compound was identified by LC-MS.

Yield: 284 mg (86%), M+1=332.0.

Reference Example 2-4 Synthesis of({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)(iminomethylthiomethyl)amine

After dissolving amino[({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)amino]methane-1-thione(148 mg, 0.446 mmol) in tetrahydrofuran (5 ml), methyl iodide (71 mg,0.491 mmol) was added and the mixture was stirred at room temperatureovernight. Upon completion of the reaction, the mixture was concentratedand dried under reduced pressure in a desiccator to obtain({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)(iminomethylthiomethyl)amine. The compound was identified by LC-MS.

Yield: 211 mg (quantitative), M+1=346.1.

Example 2-1 Synthesis of2-[({1-[(3,4-dichlorophenyl)methyl]-4-piperidyl}methyl)amino]hydroquinazolin-4-one

After dissolving({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)(iminomethylthiomethyl)amine(70 mg, 0.148 mmol) and isatoic anhydride (27 mg, 0.163 mmol) in DMF(1.5 ml), the mixture was stirred at 80° C. for 2 hours. A 2N aqueoussodium hydroxide solution (1 ml) was added to suspend the reaction.Water (15 ml) was added, and extraction was performed with ethyl acetate(15 ml×3 times). The extracted organic layer was washed with water (50ml×2 times) and then with saturated brine, dried over anhydrous sodiumsulfate, and then filtered and concentrated. Purification was performedby silica gel column chromatography (ethyl acetate/methanol=1/0→4/1) toobtain2-[({1-[(3,4-dichlorophenyl)methyl]-4-piperidyl}methyl)amino]hydroquinazolin-4-one.The compound was identified by LC-MS.

Yield: 27 mg (44%), M+1=417.1.

Examples 2-2 and 2-3

Compound Nos. 2-2 and 2-3 were synthesized by the same method as Example2-1, using the corresponding reactants. The results are shown in Table15.

Synthesis of Quinazolinone Derivatives (2) Reference Example 2-5Synthesis of 2-methylthiohydroquinazolin-4-one

After dissolving 2-mercapto-4(3H)quinazolinone (25 mmol, 4.45 g) in amixed aqueous solution of water (100 ml) and 2N NaOH (1.1 eq, 14 ml),MeI (1.1 eq, 1.72 ml) was added and the mixture was stirred at roomtemperature for 2 hours and 30 minutes. Upon completion of the reaction,the mixture was filtered, 180 ml of water was added for washing, anddrying was performed in a desiccator for 4 hours. The compound wasidentified by LC-MS.

quantitative yield, Yield: 5.5 g, M+1=192.9.

Example 2-4 Synthesis of2-({[1-(naphthylmethyl)-4-piperidyl]methyl}amino)hydroquinazolin-4-one

After dissolving [1-(naphthylmethyl)-4-piperidyl]methylamine (4.4 mmol,1122 mg) in DMA (15 ml), NEt₃ (1.5 eq, 920 μL) and2-methylthiohydroquinazolin-4-one (2 eq; 1690 mg) were added. Themixture was stirred at 100° C. overnight, and upon completion of thereaction, it was extracted with ethyl acetate (50 ml×3 times), washedwith water (150 ml×2 times), and dried over sodium sulfate. Afterconcentration, purification was performed by column chromatography(Hex/AcOEt=1/9, AcOEt×2). The compound was identified by LC-MS.

Yield: 159 mg (10%), M+1=399.3.

Synthesis of quinazolinone derivatives (3) Synthesis of[2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one hydrochlorideReference Example 2-6 Preparation of 1-Boc-4-aminomethylpiperidine

After dissolving 4-aminomethylpiperidine (10.0 g, 87.6 mmol) in toluene(175 mL), benzaldehyde (8.90 mL, 87.6 mmol) was added, a Dean-Stark trapwas fitted, and the mixture was heated to reflux for 1 hour. Thereaction mixture was cooled to room temperature, and then di-t-butyldicarbonate (20.1 mL, 87.6 mmol) was added in 4 portions over a periodof one hour, and the mixture was stirred overnight. The reaction mixturewas concentrated under reduced pressure, and then aqueous potassiumhydrogen sulfate (1.0 M, 140 mL, 140 mmol) was added to the resultingresidue in an ice bath and the mixture was stirred for 2 hours. Theaqueous solution was washed with diethyl ether (100 mL), and 1N aqueoussodium hydroxide was added to adjust the pH to approximately 7. Thisaqueous solution was washed with ethyl acetate (200 mL), and then a 1Naqueous sodium hydroxide solution was added to adjust the pH toapproximately 12 and extraction was performed with ethyl acetate (100mL×3 times). The obtained organic layer was washed with saturated brineand then dried over anhydrous sodium sulfate. It was then concentratedunder reduced pressure, and vacuum dried. The compound was identified byLC-MS.

Yield: 16.04 g (85%), M+23=237.1.

Reference Example 2-7 Synthesis of[({[fluoren-9-ylmethoxy]carbonylamino}thioxomethyl)amino]methyl]piperidinecarboxylicacid tert-butyl ester

After dissolving 1-Boc-4-aminomethylpiperidine (2140 mg, 10 mmol) intetrahydrofuran (25 ml), FmocNCS (3091 mg, 11 mmol) was added and themixture was stirred at room temperature overnight. Upon completion ofthe reaction, the reaction mixture was concentrated, and then purifiedby silica gel column chromatography (hexane/ethyl acetate=85/15→4/1) toobtain[({[fluoren-9-ylmethoxy]carbonylamino}thioxomethyl)amino]methyl]piperidinecarboxylicacid tert-butyl ester. The compound was identified by LC-MS.

Yield: 4445 mg (90%), M+1=496.2.

Reference Example 2-8 Synthesis of4-{[(aminothioxomethyl)amino]methyl}piperidinecarboxylic acid tert-butylester

After dissolving({[fluoren-9-ylmethoxy]carbonylamino}thioxomethyl)amino]methyl]piperidinecarboxylicacid tert-butyl ester (2000 mg, 4.04 mmol) in DMF (20 ml), piperidine(7.99 ml, 80.8 mmol) was added and the mixture was stirred at roomtemperature overnight. Upon completion of the reaction, water (100 ml)was added and extraction was performed with ethyl acetate (100 ml×3times). The extracted organic layer was washed with water (300 ml×2times) and saturated brine, and then dried over anhydrous sodiumsulfate, filtered out and concentrated. Purification was performed bysilica gel column chromatography (hexane/ethyl acetate=1/1→ethylacetate) to obtain4-{[(aminothioxomethyl)amino]methyl}piperidinecarboxylic acid tert-butylester. The compound was identified by LC-MS.

Yield: 1075 mg (98%), M+1=274.1.

Reference Example 2-9 Synthesis of4-{[(iminomethylthiomethyl)amino]methyl}piperidinecarboxylic acidtert-butyl ester hydroiodide

After dissolving4-{[(aminothioxomethyl)amino]methyl}piperidinecarboxylic acid tert-butylester (1075 mg, 3.94 mmol) in tetrahydrofuran (30 ml), methyl iodide(616 mg, 4.33 mmol) was added and the mixture was stirred at roomtemperature overnight. Upon completion of the reaction, the mixture wasconcentrated and dried under reduced pressure in a desiccator to obtain4-{[(iminomethylthiomethyl)amino]methyl}piperidinecarboxylic acidtert-butyl ester hydroiodide. The compound was identified by LC-MS.

Yield: 1597 mg (98%), M+1=288.1.

Reference Example 2-10 Synthesis of4-{[(4-oxohydroquinazolin-2-yl)amino]methyl}piperidinecarboxylic acidtert-butyl ester

After dissolving4-{[(iminomethylthiomethyl)amino]methyl}piperidinecarboxylic acidtert-butyl ester hydroiodide (1722 mg, 4.15 mmol) in DMF (20 ml),triethylamine (0.868 ml, 6.23 mmol) and isatoic anhydride (2029 mg,12.45 mmol) were added, and the mixture was stirred at 80° C. for 2hours. A 2N aqueous sodium hydroxide solution (10 ml) was added tosuspend the reaction. Water (100 ml) was then added, and extraction wasperformed with ethyl acetate (100 ml×3 times). The extracted organiclayer was washed with water (100 ml×2 times) and then with saturatedbrine, and was then dried over anhydrous sodium sulfate, filtered andconcentrated. Purification was performed by silica gel columnchromatography (hexane/ethyl acetate=1/1→1/2) to obtain4-{[(4-oxohydroquinazolin-2-yl)amino]methyl}piperidinecarboxylic acidtert-butyl ester. The compound was identified by LC-MS.

Yield: 685 mg (46%), M+1=359.1.

Reference Example 2-11 Synthesis of2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one hydrochloride

After dissolving4-{[(4-oxohydroquinazolin-2-yl)amino]methyl}piperidinecarboxylic acidtert-butyl ester (685 mg, 1.91 mmol) in methanol (5 ml), 4N hydrochloricacid dioxane (5 ml) was added and the mixture was stirred at roomtemperature overnight. Upon completion of the reaction, the mixture wasconcentrated and dried under reduced pressure in a desiccator to obtain2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one hydrochloride. Thecompound was identified by LC-MS.

Yield: 581 mg (quantitative), M+1=259.1.

Synthesis of [2-[(4-piperidylmethyl)amino]hydroquinazolin-4-oneReference Example 2-12 Synthesis of (1-benzyl-4-piperidyl)methylamine

After dissolving 4-aminomethylpiperidine (5.754 ml, 50 mmol) inacetonitrile (200 ml), potassium carbonate (13.82 g, 100 mmol) andbenzyl chloride (17.13 g, 150 mmol) were added and the mixture wasstirred at 60° C. overnight. Upon completion of the reaction, thereaction mixture was filtered and the solvent was distilled off. Adeveloping solvent (CH₂Cl₂/MeOH/NEt₃ 90/5/5) was used for purificationby silica gel column chromatography to obtain(1-benzyl-4-piperidyl)methylamine. The compound was identified by LC-MS.

Yield: 9.277 g (91%), M+1=205.2.

Reference Example 2-13 Synthesis of2-({[1-benzyl-4-piperidyl]methyl}amino)hydroquinazolin-4-one

The (1-benzyl-4-piperidyl)methylamine was used to synthesize2-({[1-benzyl-4-piperidyl]methyl}amino)hydroquinazolin-4-one in the samemanner as Reference Examples 2-7 (Yield: 84%), 2-8 (Yield: 73%), 2-9(quantitative yield) and 2-10 (Yield: 73%).

Reference Example 2-14 Synthesis of2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one

After dissolving2-({[1-benzyl-4-piperidyl]methyl}amino)hydroquinazolin-4-one (880 mg,2.53 mmol) in methanol (80 mL), nitrogen substitution was carried out.Palladium hydroxide (100 mg) was added and the mixture was stirred at60° C. for 4 hours under a hydrogen atmosphere. The reaction mixture wascooled to room temperature, nitrogen substitution was carried out, andfiltration was performed through celite. The filtrate was concentratedunder reduced pressure to obtain2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one. The compound wasidentified by LC-MS.

Yield: 588 mg (86%), M+1=259.1.

Example 2-5 Synthesis of2-[({1-[(2-chlorophenyl)methyl]-4-piperidyl}methyl)amino]hydroquinazolin-4-one

After dissolving 2-[(4-piperidylmethyl)amino]hydroquinazolin-4-onehydrochloride (0.1 mmol, 33 mg, Reference Example 2-11) or2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one (0.1 mmol) inDMF/acetic acid (10/1, 1 ml), 2-chlorobenzaldehyde (0.3 mmol, 0.034 ml)and NaBH(OAc)₃ (0.3 mmol, 64 mg) were added and the mixture was stirredat room temperature overnight. Next, 1 ml of MeOH was added to suspendthe reaction. The reaction mixture was then poured into SCX (Bond EluteSCX500MG). After washing with CHCl₃/MeOH (=1/1, 5 ml×2 times), elutionwas performed with 5 ml of a 2N NH₃/MeOH solution. A centrifugalconcentrator was used for distilling off of the solvent to obtain2-[({1-[(2-chlorophenyl)methyl]-4-piperidyl}methyl)amino]hydroquinazolin-4-one.

Yield: 15 mg (39%), Purity: 92-96% M+1=383.1.

Examples 2-6 to 2-30, Examples 2-186 to 2-200

Compound Nos. 2-6 to 2-30 and Compound Nos. 2-186 to 2-200 weresynthesized by the same method as Example 2-5, using the correspondingreactants. The results are shown in Table 15.

Synthesis of [2-[(4-piperidylmethyl)amino]hydroquinazolin-4-onehydrochloride analogs Reference Example 2-15 Synthesis of2-amino-5-(methoxycarbonyl)benzoic acid

After dissolving 2-amino-5-iodobenzoic acid (4 mmol, 1052 mg) in DMF (10ml) and MeOH (5 ml), NEt₃ (3 eq, 1.67 ml) was added. Next, palladiumacetate (0.1 eq, 90 mg) and dppp (0.1 eq, 165 mg) were added, carbonmonoxide substitution was carried out, and the mixture was stirred at80° C. for 5 hours. Upon completion of the reaction, acetic acid (2.5ml) was added to suspend the reaction. Water (50 ml) was added, andextraction was performed with ethyl acetate (50 ml×3 times). The organiclayer was washed with water (100 ml×2 times) and then dried over sodiumsulfate. After concentration, a developing solvent (Hex/AcOEt=4/1→1/1)was used for purification by silica gel chromatography to obtain2-amino-5-(methoxycarbonyl)benzoic acid. The compound was identified byLC-MS.

Yield: 618 mg (79%), M+1=196.0.

Synthesis of Substituted Isatoic Anhydrides (1) Reference Example 2-16Synthesis of 2-(Boc)amino-6-chlorobenzoic acid

After dissolving 2-amino-6-chlorobenzoic acid (1.13 g, 6.59 mmol) intetrahydrofuran (5.0 mL), a solution of sodiumbistrimethylsilylamide/1.0 M in THF (19.8 mL, 19.8 mmol) was addeddropwise. After stirring this mixture for 15 minutes, a solution of(Boc)₂O (1.82 mL, 7.91 mmol) in tetrahydrofuran (2.0 mL) was addeddropwise, and the mixture was stirred for 3 hours. Water (20 mL) and 1Nhydrochloric acid (about 25 mL) were added to the reaction mixture toadjust the pH to approximately 4. It was then extracted with ethylacetate (40 mL×3 times), and the obtained organic layer was washed withwater (50 mL×2 times) and saturated brine (50 mL), and then dried overanhydrous magnesium sulfate. The dried product was concentrated underreduced pressure to obtain a concentrated residue, which was thenpurified by silica gel column chromatography (methylenechloride:methanol:acetic acid=95:5:1) to obtain2-(Boc)amino-6-chlorobenzoic acid. The compound was identified by LC-MSand NMR.

Yield: 1.62 g (90%), M+23=294.0.

¹H-NMR (270 MHz, CDCl₃): δ8.40(1H, s), 8.04(1H, d, J=8.2 Hz), 7.35(1H,t, J=8.2 Hz), 7.13(1H, d, J=8.2 Hz), 1.52(9H, s) ppm.

The following intermediates were synthesized by the same method asReference Example 2-16, using the corresponding reactants.

-   2-(Boc)amino-3-chlorobenzoic acid: Yield=3.58 g (70%), M+23=294.0.-   2-(Boc)amino-5-methoxycarbonylbenzoic acid: Yield=988 mg (49%),    M+1=296.1.

Reference Example 2-17] Synthesis of 5-chloroisatoic anhydride

After suspending 2-(Boc)amino-6-chlorobenzoic acid (1.51 g, 5.56 mmol)in toluene (20 mL), the mixture was heated to reflux. Oxalyl chloride(0.572 mL, 6.67 mmol) was added dropwise thereto, and the mixture wasvigorously stirred for 10 minutes. After cooling the reaction mixture onice, the precipitated crystals were filtered out, washed with n-hexaneand dried in a desiccator to obtain 5-chloroisatoic anhydride.

Yield: 769 mg (70%), M+1=198.0.

¹H-NMR (270 MHz, DMSO-d6): δ11.8(1H, s), 7.65(1H, t, J=8.2 Hz), 7.30(1H,d, J=8.2 Hz), 7.10(1H, d, J=8.2 Hz) ppm.

The following intermediates were synthesized by the same method asReference Example 2-17, using the corresponding reactants.

-   8-Chloroisatoic anhydride: Yield=1.42 g (55%), M+1=197.9.-   6-Methoxycarbonylisatoic anhydride: Yield=397 mg (57%), M+1=222.0.-   6-Trifluoromethylisatoic anhydride: Yield=1.52 g (50%), M+1=232.0.

Synthesis of Substituted Isatoic Anhydrides (2) Reference Example 2-18Synthesis of 6-(trifluoromethoxy)isatoic anhydride

After dissolving 5-(trifluoromethoxy)anthranilic acid (2.221 g, 10.04mmol) in THF (25 mL), triphosgene (1.08 g) was added and the mixture wasstirred at room temperature overnight. Upon completion of the reaction,the solvent was removed and the residue was dried under reducedpressure. It was then washed with acetone and hexane, and subsequentlydried under reduced pressure in a desiccator to obtain6-(trifluoromethoxy)isatoic anhydride. The compound was identified byLC-MS.

Yield: 1.516 g (61%), M+1=248.0.

The following intermediates were synthesized in the same manner asReference Example 2-18 using the corresponding reactants.

-   6-Nitroisatoic anhydride: Yield=0.889 g (43%), M+1=208.9.-   6-Methylisatoic anhydride: Yield=1.251 g (70%), M+1−178.0.-   5-Carboxylisatoic anhydride: Yield=1.352 g (65%), M+1=208.0.-   6-Fluoroisatoic anhydride: M+1=182.0.-   6-Hydroxyisatoic anhydride: M+1=180.0.-   6-Methoxyisatoic anhydride: M+1=194.0.-   5-Methylisatoic anhydride: M+1=178.0.-   6-Acetamideisatoic anhydride: Yield=0.4 g (9%),

¹H-NMR (200 MHz, DMSO): δ2.05(s, 3H), 7.05(d, 1H), 7.85(dd, 1H), 8.25(d,1H), 10.15(s, 1H).

Synthesis of Substituted Isatoic Anhydrides (3) Reference Example 2-19Synthesis of N-(3,4-dimethylphenyl)-2-hydroxyimino-acetamide

To a mixed solution comprising a solution of chloral (73.8 g, 0.41 mol)and sodium sulfate (1066 g) in water (2.5 ml) and a solution of3,4-dimethylamine (50 g, 0.41 mol) and concentrated hydrochloric acid(35.4 ml) in water (600 ml) there was added a solution of hydroxylamine(90 g, 0.41 mmol) in water (500 ml), and the mixture was stirred for onehour while heating to reflux. The obtained hot solution was filtered,and the obtained precipitate was washed with water and dichloromethaneto obtain N-(3,4-dimethylphenyl)-2-hydroxyimino-acetamide.

Yield: 63 g (80%).

Reference Example 2-20 Synthesis of 4,5-dimethyl-1H-indole-2,3-dione

To a solution of concentrated sulfuric acid (85 ml) in water (17 ml)there was slowly added N-(3,4-dimethylphenyl)-2-hydroxyimino-acetamide(30 g, 0.156 mmol), and the mixture was stirred at 85° C. for 2 hours.The obtained solution was poured into ice water, and the precipitatedorange solid was filtered out. The obtained solid was dissolved in 10%aqueous sodium hydroxide, active carbon was added, and the mixture wasstirred. The obtained solution was filtered, and acetic acid was usedfor acidification to obtain 4,5-dimethyl-1H-indole-2,3-dione ascrystals.

Yield: 9:8 g (30%)

¹H-NMR (200 MHz, DMSO-d6): 2.25(s, 3H), 2.55(s, 3H), 6.95(d, 2H),7.50(d, 2H), 10.55(bs, 1H)

Reference Example 2-21 Synthesis of 6-amino-2,3-dimethylbenzoic acid

A solution of 4,5-dimethyl-1H-indole-2,3-dione (9.8 g, 0.056 mmol) andsodium hydroxide (8.1 g, 0.2 mol) in water (80 ml) was heated to 85° C.,and then 10% aqueous hydrogen peroxide (43 ml) was slowly added. Theobtained solution was stirred at 85° C. for 2 hours and then cooled toroom temperature and filtered. Sulfuric acid was used for acidificationof the filtrate to obtain 6-amino-2,3-dimethylbenzoic acid as crystals.

Yield: 3.6 g (38%)

¹H-NMR (200 MHz, DMSO-d6): 2.05(s, 3H), 2.15(s, 3H), 6.50(d, 2H),6.92(d, 2H)

Reference Example 2-22 Synthesis of 5,6-dimethylisatoic anhydride

5,6-Dimethylisatoic anhydride was synthesized by the same method asReference Example 2-18 using 6-amino-2,3-dimethylbenzoic acid (1 g, 6mmol).

Yield: 500 mg (92%)

¹H-NMR (200, DMSO): 2.25(s, 3H), 2.55(s, 3H), 6.92(d, 2H), 7.50(d, 2H),10.65(bs, 1H)

The following isatoic anhydrides were synthesized by the same method asReference Examples 2-19 to −22, using the corresponding reactants.

-   5-Methyl-6-fluoroisatoic anhydride:

¹H-NMR (200 MHz, DMSO-d6): 2.45(s, 3H), 6.75(dd, 1H), 7.45(dd, 1H),11.0(bs, 1H)

-   5-Methyl-6-bromoisatoic anhydride:

¹H-NMR (200, DMSO): 2.75(s, 3H), 6.85(d, 1H), 7.95(d, 1H), 10.75(bs, 1H)

-   6-(N,N-dimethylaminosulfonyl)isatoic anhydride:

¹H-NMR (200 MHz, DMSO-d6): 2.65(s, 6H), 7.35(d, 1H), 8.05(s, 1H),8.15(d, 1H), 11.2(bs, 1H)

-   6-Methoxy-7-methylisatoic anhydride:

M+1=208.0

-   5-Methyl-6-methoxyisatoic anhydride:

M+1=208.0

-   6,7-Dimethylisatoic anhydride:

¹H-NMR (200, DMSO): 2.24(s, 3H), 2.29(s, 3H), 6.91(s, 1H), 7.66(s, 1H),10.60(bs, 1H).

-   5,7-Dimethylisatoic anhydride:

¹H-NMR (200 MHz, DMSO-d6): 6.91(s, 1H), 6.79(s, 1H), 2.56(s, 3H),2.32(s, 3H)

-   6-Ethylisatoic anhydride:

¹H-NMR (200, DMSO): 7.73(s, 1H), 7.65(d, 1H), 7.09(d, 1H), 2.64(q, 2H),1.18(t, 3H)

-   6-Ethoxyisatoic anhydride:

¹H-NMR (200 MHz, DMSO-d6): 1.35(t, 3H), 4.05(q, 2H), 7.05(d, 1H),7.35(d, 1H), 7.45(dd, 1H), 10.5(bs, 1H)

-   5-Methyl-8-fluoroisatoic anhydride:

¹H-NMR (200 MHz, DMSO-d6): 2.56(s, 3H), 7.05(dd, 1H), 7.55(dd, 1H)

-   5,8-Dimethylisatoic anhydride:

¹H-NMR (200 MHz, DMSO-d6): 2.27(s, 3H), 2.56(s, 3H), 7.00(d, 1H),7.45(d, 1H)

-   6-Isopropylisatoic anhydride:

¹H-NMR (200, DMSO): 7.73(s, 1H), 7.65(d, 1H), 7.10(d, 1H), 2.95(h, 1H),1.20(d, 6H)

-   6-Sulfonylphenylisatoic anhydride:

¹H-NMR (200 MHz, DMSO-d6): 7.35(d, 1H), 7.65(m, 3H), 8.00(m, 2H),8.25(dd, 1H), 8.35(d, 1H), 11.30(s, 1H)

Synthesis of Substituted Isatoic Anhydrides (4) Reference Example 2-23Synthesis of 2-amino-5-methylsulfanylbenzoic acid

A 4N aqueous sodium hydroxide solution (42 m) was added to an aqueoussolution (500 ml) containing 5-chloro-2-nitrobenzoic acid (50 g, 0.25mmol). After adding a solution of Na₂S (66 g, 0.8 mol) in water (150 ml)to the obtained solution, the mixture was stirred at 55° C. for 2.5hours. Next, a 20% aqueous sodium hydroxide solution (50 ml) anddimethylsulfuric acid (63 ml, 0.66 mmol) were added to the solution, andthe mixture was stirred at 80° C. for 1 hour. Hydrochloric acid wasadded to the resulting solution, and the separated precipitate wasfiltered out and washed with ether to obtain2-amino-5-methylsulfanylbenzoic acid.

Yield: 14 g (26%)

Reference Example 2-24 Synthesis of 2-amino-5-methylsulfonylbenzoic acid

m-Chloroperbenzoic acid (42.7 g, 0.165 mmol) was added to a solution of2-amino-5-methylsulfanylbenzoic acid (12 g, 0.055 mol) indichloromethane and acetone, and the mixture was stirred at roomtemperature for 3 hours. The precipitated solid was filtered out andwashed with ether and dichloromethane to obtain2-amino-5-methylsulfonylbenzoic acid.

Yield: 4 g (30%)

¹H-NMR (200 MHz, DMSO-d6): 3.15(s, 3H), 6.95(dd, 1H), 7.55(bs, 2H),7.77(dd, 1H), 8.25(d, 1H)

Reference Example 2-25 Synthesis of 6-methanesulfonylisatoic anhydride

6-Methanesulfonylisatoic anhydride was synthesized by the same method asReference Example 11 using 2-amino-5-methylsulfonylbenzoic acid (2 g,9.6 mmol).

Yield: 1500 mg (66%)

¹H-NMR (200 MHz, DMSO-d6): 3.35(s, 3H), 7.35(d, 1H), 8.25(dd, 1H),8.35(d, 1H), 9.90(s, 1H)

Reference Example 2-26 Synthesis of2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one hydrochloride analogs

The following intermediates were synthesized in the same manner asReference Example 2-10 and Reference Example 2-11, for the isatoicanhydrous synthesized by Reference Example 2-17 or 2-18.

-   5-Chloro-2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one    hydrochloride.-   8-Chloro-2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one    hydrochloride.-   6-Methoxycarbonyl-2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one    hydrochloride.-   6-Trifluoromethyl-2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one    hydrochloride.-   6-Trifluoromethoxy-2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one    hydrochloride.-   6-Nitro-2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one    hydrochloride.-   6-Methyl-2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one    hydrochloride.-   5-Methoxycarbonyl-2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one    hydrochloride.-   6-Fluoro-2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one    hydrochloride.-   6-Hydroxy-2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one    hydrochloride.-   6-Methoxy-2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one    hydrochloride.-   5-Methyl-2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one    hydrochloride.

Examples 2-201 to 2-250, 499, 511, 513, 565

Compound Nos. 2-201 to 2-250, 499, 511, 513 and 565 were synthesized bythe same method as Example 2-5, using the corresponding synthesized2-[(4-piperidylmethyl)amino]hydroquinazolin-4-one hydrochloride analogsand reactants of Reference Examples 2-15 to 2-19. The results are shownin Table 15.

Synthesis of 3-N-alkylquinazolinone derivatives Reference Example 2-27Synthesis of 4-({[(methylamino)thioxomethyl]amino}methyl) piperidinecarboxylic acid tert-butyl ester

After dissolving 1-Boc-4-aminomethylpiperidine (642 mg, 3 mmol) in THF(8 ml), methyl isothiocyanate (241 mg, 3.3 mmol) was added and themixture was stirred at room temperature overnight. Upon completion ofthe reaction, purification was performed by silica gel columnchromatography (Hex/AcOEt=1/4) to obtain4-({[(methylamino)thioxomethyl]amino}methyl)piperidine carboxylic acidtert-butyl ester. The compound was identified by LC-MS.

Yield: 839 mg (98%), M+1=288.1.

Reference Example 2-28 Synthesis of3-methyl-2-[(4-piperidylmethyl)amino]-3-hydroquinazolin-4-onehydrochloride

3-Methyl-2-[(4-piperidylmethyl)amino]-3-hydroquinazolin-4-onehydrochloride was synthesized in the same manner as Reference Example2-9 (Yield: 1171 mg (94%)), Reference Example 2-10 (Yield: 331 mg (33%))and Reference Example 2-11 (Yield: 116 mg, quantitative).

Yield: 116 mg (quantitative), M+1=273.1.

Examples 2-492 to 2-495

Compound Nos. 2-492 to 2-495 were synthesized by the same method asExample 2-5, using the corresponding reactants for the compoundssynthesized by Reference Examples 2-20 and 2-21. The results are shownin Table 15. TABLE 15 Compound No. 2- Yield (mg) Yield (%) MW M + 1 127.0 44 416.1 417.1 2 25.0 38 450.1 453.2(Cl × 3) 3 4.1 6 432.2 433.2 4159.0 10 398.2 399.3 5 15.0 39 382.1 383.1 6 21.0 55 382.1 383.1 7 25.065 382.1 383.1 8 23.3 92 378.2 379.1 9 36.0 100 378.2 379.1 10 22.6 97376.2 377.2 11 23.2 97 398.2 399.1 12 25.3 95 442.1 443.0 13 27.7 100456.1 458.1(Br) 14 19.3 72 444.1 445.0 15 24.8 97 426.1 427.1 16 23.3 90432.1 433.1 17 23.3 97 400.1 401.1 18 24.3 90 401.2 402.2 19 29.1 100404.2 405.2 20 11.9 50 394.2 395.2 21 13.1 55 393.2 394.2 22 12.1 53378.2 379.2 23 17.0 71 398.2 399.2 24 12.5 60 348.2 349.2 25 7.6 35362.2 363.2 26 1.6 3 476.0 479.0(Br) 27 6.0 15 389.2 390.2 28 12.0 30466.1 467.2 29 12.0 28 466.1 467.1 30 14.0 40 398.2 399.1 186 15.0 57432.1 433.0 187 25.8 95 443.1 444.1 188 25.0 96 428.2 429.1 189 21.6 85416.1 417.1 190 22.6 80 460.1 463.0(Br, Cl) 191 24.4 93 427.1 428.1 19226.6 96 412.2 413.1 193 21.3 75 466.1 467.1 194 17.2 65 435.2 436.2 19524.2 90 438.1 439.1 196 21.4 92 382.2 383.1 197 22.5 90 410.2 411.1 19816.5 57 476.1 479(Br, Cl) 199 7.8 30 432.2 433.1 200 6.3 26 396.2 397.1201 1.0 5 466.1 469.1(Cl × 3) 202 4.7 34 462.1 463.0 203 4.0 21 490.1491.1 204 4.8 34 466.1 469.1(Cl × 3) 205 2.0 41 490.1 491.0 206 2.5 14466.1 467.0 207 2.8 14 516.1 517.1 208 2.9 15 490.1 491.1 209 3.9 19500.1 501.1 210 2.4 12 446.1 447.1 211 5.0 26 450.1 451.1 212 2.5 13448.1 449.0 213 4.0 9 477.1 478.0 214 20.0 37 468.1 469.1 215 7.0 13450.1 451.0 216 2.8 6 446.1 447.1 217 3.0 8 457.1 458.1 218 2.2 13 432.1433.0 219 9.5 74 428.2 429.3 220 5.5 31 456.2 457.1 221 5.2 40 432.1433.1 222 3.1 68 456.2 457.2 223 6.7 40 432.1 433.1 224 5.0 27 482.1483.1 225 3.5 20 456.2 457.2 226 3.4 18 466.1 467.1 227 3.0 17 412.2413.1 228 5.9 33 416.1 417.0 229 4.0 23 432.2 433.1 230 2.0 23 428.2429.2 231 1.0 6 456.2 457.2 232 1.6 9 432.2 433.2 233 1.7 9 456.2 457.3234 7.2 43 432.2 433.1 235 8.5 46 482.2 483.1 236 2.6 15 456.2 457.2 2372.0 11 466.2 467.2 238 3.7 21 412.2 413.2 239 5.3 30 416.2 417.1 240 6.338 410.2 411.2 241 2.9 36 406.2 407.3 242 9.2 55 434.2 435.2 243 10.2 62410.2 411.2 244 21.1 121 434.2 435.2 245 10.0 63 410.2 411.1 246 15.7 89460.2 461.2 247 2.1 13 434.2 435.2 248 5.8 33 444.2 445.2 249 4.4 26390.2 391.2 250 7.6 45 394.2 395.1 492 5.0 17 446.1 447.1 493 9.0 31412.2 413.2 494 16.0 55 412.2 413.2 495 15.0 52 390.2 391.2 499 12.0 38430.9 431.1 511 10.0 32 434.9 435.1 513 6.0 16 430.9 431.1 565 9.2 26442.9 443.1

Synthesis of Benzothiadiazine Derivatives Reference Example 3-1Synthesis of 7-fluoro-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione

After dissolving chlorosulfonyl isocyanate (3.29 mL, 37.8 mmol) innitroethane (45 mL), the mixture was cooled to −80° C. A solution of4-fluoroaniline (3.50 g, 31.5 mmol) in nitromethane (5 mL) was thenadded dropwise thereto over a period of 10 minutes. The reaction mixturewas heated to 0° C., and aluminum chloride (5.33 g, 40.0 mmol) wasadded. After heating to reflux for 30 minutes, the reaction mixture wascooled to room temperature and then poured into ice water (120 mL). Theprecipitated crystals were filtered out and dried to obtain7-fluoro-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione.

Yield: 3.72 g (55%), M+1=217.0.

7-Methyl-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione (4.24 g, 67%),7-ethyl-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione (2.6 g, 37%) and7-methoxy-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione (1.09 g, 16%)were synthesized in the same manner as Reference Example 3-1.

Reference Example 3-2 Synthesis of 2-amino-5-fluorobenzenesulfonamide

After suspending 7-fluoro-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione(3.00 g, 13.9 mmol) in 50% sulfuric acid (90 mL), the mixture wasstirred at 130° C. for 1 hour. The reaction mixture was cooled in an icebath while adding 40% aqueous sodium hydroxide for neutralization. Theaqueous solution was concentrated under reduced pressure to 200 mL, andthe precipitate was filtered out. It was then suspended in ethyl acetate(100 mL), and the insoluble portion was filtered out. The filtrate wasconcentrated under reduced pressure and dried to obtain2-amino-5-fluorobenzenesulfonamide.

Yield: 2.27 g (86%), M+1=191.0.

2-Amino-5-methylbenzenesulfonamide (Yield: 958 mg (55%)),2-amino-5-ethylbenzenesulfonamide (Yield: 1.4 g (64%)) and2-amino-5-methoxybenzenesulfonamide (Yield: 696 mg (72%)) weresynthesized in the same manner as Reference Example 3-2.

Reference Example 3-3 Synthesis of 2-bromo-4,5-dimethylnitrobenzene

After measuring out 10.02 g of 4,5-dimethyl-2-nitroaniline (60.3 mmol)into a 300 mL round-bottomed flask equipped with a magnetic stirrer, 30mL of 48% aqueous hydrobromic acid and 30 mL of water were added, andthe mixture was vigorously stirred. The suspension became orange. Theorange suspension was directly cooled on an ice water-salt bath, andthen an aqueous solution of 4.422 g (64.1 mmol) of sodium nitrite in 24mL of water was added dropwise to the orange suspension while keepingthe liquid temperature from exceeding 5° C. Completion of the dropwiseaddition resulted in conversion of the reaction mixture to a light brownsolution. The light brown solution was stirred on the ice water bath.

Next, 30 mL of 48% aqueous hydrobromic acid and 11.85 (82.6 mmol) g ofcopper (I) bromide were placed in a 1 L Erlenmeyer flask equipped with amagnetic stirrer, and the previously obtained light brown solution wasadded dropwise over a period of 5 minutes while cooling and stirring onan ice water bath. After completion of the dropwise addition, themixture was stirred for 20 minutes on the ice-water bath, and thenheated on a 80° C. oil bath while vigorously stirring.

Heating was terminated after 1 hour, and upon stirring overnight at roomtemperature, the reaction mixture was extracted with ethyl acetate (300mL×2 times), and the organic layers were combined and washed with 5Nhydrochloric acid, saturated sodium bicarbonate water and saturatedbrine in that order. The organic layer was dried over anhydrous sodiumsulfate, and then the desiccant was removed by filtration under reducedpressure and the filtrate was concentrated to obtain a yellowish brownsolid. The yellowish brown solid was purified by silica gel columnchromatography (Hex:EtOAc=10:1) to obtain light brown needle-likecrystals. The light brown needle-like crystals were recrystallized fromhexane to obtain 2-bromo-4,5-dimethylnitrobenzene as yellow needle-likecrystals.

Yield: 6.637 g (47.9%)

¹H-NMR (270 MHz, CDCl₃): δ2.29(3H, s), 2.31(3H, s), 7.49(1H, s),7.69(1H, s).

Reference Example 3-4 Synthesis of 2-bromo-4,5-dimethylaniline

After measuring out 1.006 g (4.375 mmol) of2-bromo-4,5-dimethylnitrobenzene into a 100 mL round-bottomed flaskequipped with a magnetic stirrer, 10 mL of 2-methoxyethanol and 10 mL ofwater were added and the mixture was stirred to create a suspension.After adding 2.799 g (10.07 mmol) of sodium hydrosulfite thereto, it washeated on a 100° C. oil bath while vigorously stirring. After 2.5 hours,the resulting faint yellow suspension was heated and stirred, whileadding 10 mL of water until the insoluble portion disappeared to producea faint yellow solution. To the faint yellow solution there was addeddropwise 10 mL of concentrated hydrochloric acid over a period of 5minutes, after which the mixture was refluxed for 20 minutes.

Next, the temperature of the reaction mixture was lowered to roomtemperature, and upon adding sodium carbonate in powder form toneutralize the reaction mixture, a faint brownish white precipitateseparated at approximately pH 7-8. The collected precipitate was driedto obtain 2-bromo-4,5-dimethylaniline as a white solid.

Yield: 0.832 g (95.0%).

¹H-NMR (270 MHz, CDCl₃): δ2.13(6H, s), 6.59 (1H, s), 7.16(1H, s).

Reference Example 3-5 Synthesis of5-bromo-7,8-dimethyl-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione

The title compound was obtained in the same manner as Reference Example3-1.

Yield: 5.27 g (83%), M+1=304.9.

¹H-NMR (270 MHz, CD₃OD): δ7.69(1H, s), 2.55(3H, s), 2.31(3H, s)

Reference Example 3-6 Synthesis of7,8-dimethyl-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione

5-Bromo-7,8-dimethyl-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione (5.27g, 17.3 mmol) was suspended in methanol (60 mL), and then ammoniumformate (5.45 g, 86.5 mmol, 5 eq) was added and nitrogen substitutionwas performed. Next, 10% palladium-carbon powder (1.84 g, 1.73 mmol, 10mol %) was added and the mixture was heated to reflux for 4 hours. Thereaction mixture was cooled to room temperature and filtered throughcelite. The filtrate was cooled on ice and the precipitated crystalswere filtered out and dried to obtain 7,8-dimethyl-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione.

Yield: 3.66 g (94%), M+1=227.0.

¹H-NMR (270 MHz, CD₃OD): δ7.19(1H, d, J=8.3 Hz), 6.78(1H, d, J=8.3 Hz),2.57(3H, s), 2.26(3H, s).

Reference Example 3-7 Synthesis of2-amino-5,6-dimethylbenzenesulfonamide

The title compound was obtained in the same manner as Reference Example3-2.

Yield: 1.98 g (61%), M+1=201.1.

¹H-NMR (270 MHz, DMSO-d6): δ7.20(2H, s), 6.98(1H, d, J=8.4 Hz), 6.55(1H,d, J=8.4 Hz), 5.98(2H, s), 2.39(3H, s), 2.10(3H, s)2-Amino-6-methylbenzenesulfonamide was synthesized in the same manner asReference Examples 3-3 to 3-7, using 4-methyl-2-nitroaniline as thestarting material.

Yield: 555 mg (45%).

¹H-NMR (270 MHz, DMSO): δ2.48(3H, s), 6.12(2H, s), 6.40(1H, d, J=7.0Hz), 6.62(1H, d, J=8.1 Hz), 6.99-7.04(1H, dd, J=8.1 Hz, J=7.0 Hz),7.19(2H, s)

Reference Example 3-8 Synthesis of4-{[(7-fluoro-1,1-dioxo-4H-benzo[e]1,2,4-thiadiazin-3-yl)amino]methyl}piperidinecarboxylic acid tert-butyl ester

After dissolving 1-N-Boc-4-aminomethylpiperidine (1.08 g, 5.04 mmol) inacetonitrile (8.0 mL), the mixture was cooled to 0° C. A solution of1,1′-thiocarbonyldiimidazole (988 mg, 5.54 mmol) and imidazole (103 mg,1.51 mmol) in acetonitrile (10 mL) was added dropwise thereto, and themixture was stirred at room temperature for 2 hours. Next,2-amino-5-fluorobenzenesulfonamide (1.25 g, 6.55 mmol) anddimethylaminopyridine (739 mg, 6.05 mmol) were added to the reactionmixture, which was then stirred at 80° C. overnight.Diisopropylcarbodiimide (0.233 mL, 1.51 mmol) was added thereto, and themixture was stirred for 1 hour. The reaction mixture was cooled to roomtemperature and then concentrated under reduced-pressure, and theresidue was dissolved in ethyl acetate (50 mL). This was washed withwater (20 mL) and saturated brine (20 mL), and then dried over anhydroussodium sulfate. The residue obtained by concentration under reducedpressure was purified by silica gel column chromatography(n-hexane:ethyl acetate=3:2→2:3) to obtain4-{[(7-fluoro-1,1-dioxo-4H-benzo[e]1,2,4-thiadiazin-3-yl)amino]methyl}piperidinecarboxylic acid tert-butyl ester.

Yield: 1.66 g (80%), M-Boc+2H=313.1.

The following compounds were synthesized in the same manner as ReferenceExample 3-8.

-   4-7{[(1,1-Dioxo-4H-benzo[e]1,2,4-thiadiazin-3-yl)amino]methyl}piperidine    carboxylic acid tert-butyl ester: Yield=132 mg (67%).-   4-{[(7-Methyl-1,1-dioxo-4H-benzo[e]1,2,4-thiadiazin-3-yl)amino]methyl}piperidine    carboxylic acid tert-butyl ester: Yield=681 mg (49%).-   4-{[(7-Methoxy-1,1-dioxo-4H-benzo[e]1,2,4-thiadiazin-3-yl)amino]methyl}piperidine    carboxylic acid tert-butyl ester: Yield=766 mg (63%).-   4-{[(7-Ethyl-1,1-dioxo-4H-benzo[e]1,2,4-thiadiazin-3-yl)amino]methyl}piperidine    carboxylic acid tert-butyl ester: Yield=525 mg (36%).-   4-{[(8-Methyl-1,1-dioxo-4H-benzo[e]1,2,4-thiadiazin-3-yl)amino]methyl}piperidine    carboxylic acid tert-butyl ester: Yield=203 mg (44%).-   4-{[(7,8-Dimethyl-1,1-dioxo-4H-benzo[e]1,2,4-thiadiazin-3-yl)amino]methyl}piperidine    carboxylic acid tert-butyl ester: Yield=175 mg (30%).

Reference Example 3-9 Synthesis of7-fluoro-3-[(4-piperidylmethyl)amino]-4H-benzo[e]1,2,4-thiadiazine-1,1-dionehydrochloride

7-fluoro-3-[(4-piperidylmethyl)amino]-4H-benzo[e]1,2,4-thiadiazine-1,1-dionewas obtained in the same manner as Reference Example 2-11. Yield: 497 mg(90%), M+1=313.1.

The following compounds were synthesized in the same manner as ReferenceExample 3-9.

-   7-Methyl-3-[(4-piperidylmethyl)amino]-4H-benzo[e]1,2,4-thiadiazine-1,1-dione    hydrochloride: Yield=691 mg (quantitative).-   3-[(4-Piperidylmethyl)amino]-4H-benzo[e]1,2,4-thiadiazine-1,1-dione    hydrochloride: quantitative yield, Yield=116 mg, M+1=295.1.-   7-Methoxy-3-[(4-piperidylmethyl)amino]-4H-benzo[e]1,2,4-thiadiazine-1,1-dione    hydrochloride: Yield=505 mg (79%), M+1=325.0.-   7-Ethyl-3-[(4-piperidylmethyl)amino]-4H-benzo[e]1,2,4-thiadiazine-1,1-dione    hydrochloride: Yield=470 mg (quantitative, M+1=323.1).-   8-Methyl-3-[(4-piperidylmethyl)amino]-4H-benzo[e]1,2,4-thiadiazine-1,1-dione    hydrochloride: Yield=97 mg (63%), M+1=309.1.-   7,8-Dimethyl-3-[(4-piperidylmethyl)amino]-4H-benzo[e]1,2,4-thiadiazine-1,1-dione    hydrochloride: Yield=44 mg (89%), M+1=323.1.

Examples 3-1 to 3-10, 3-208, 220, 223, 235, 238, 368, 504, 505, 511,523, 525 to 527, 555, 577

Compound Nos. 3-1 to 3-10, 3-208, 220, 223, 235, 238, 368, 504, 505,511, 523, 525 to 527, 555 and 577 were synthesized in the same manner asExample 2-5, using the corresponding reactants for the compoundssynthesized in Reference Examples 3-1 to 3-9. The results are shown inTable 16. TABLE 16 Compound Yield No. 3- (mg) Yield (%) MW M + 1 1 10.035 468.0 469.0 2 7.0 26 434.1 435.1 3 9.0 34 434.1 435.0 4 13.0 52 412.1413.1 5 25.2 66.2 482.1 483.0 6 20.8 58.9 448.1 449.1 7 25.4 71.9 448.2449.2 8 9.9 26.1 486.1 487.0 9 20.5 58.1 452.1 453.1 10 38.3 100 452.2453.1 208 20.4 54 499.4 499.0 220 4.7 11 483.4 483.0 223 28.7 81 465.0465.1 235 8.1 21 449.0 449.1 238 34.1 97 464.6 465.2 368 4.5 12 463.0463.1 504 4.0 13 497.4 497.1 505 10.0 35 463.0 463.1 511 9.8 24 467.0467.0 523 15.0 50 470.9 471.1 525 5.4 13 467.0 467.1 526 8.0 27 481.0481.1 527 18.0 60 483.0 483.1 555 17.2 37 481.0 481.1 577 9.4 25 479.1479.0

Synthesis of Dihydroquinazoline Derivatives Reference Example 4-1Synthesis of 4-(dihydroquinazoline-2-aminomethyl)piperidinehydrochloride

After dissolving 1-Boc-4-(aminomethyl)piperidine (350 mg, 1.6 mmol) inCH₃CN (15 ml), thiocarbonyldiimidazole (350 mg, 1.9 mmol) was added andthe mixture was stirred at room temperature for 1 hour.2-Aminobenzylamine (240 mg, 1.9 mmol) was added to the reaction mixture,which was then stirred at room temperature for one hour. The solvent wasdistilled off under reduced pressure to obtain1-Boc-4-(2-aminobenzylthioureamethyl)piperidine. The compound wasidentified by LC-MS.

M+1=379.2.

After dissolving the 1-Boc-4-(2-aminobenzylthioureamethyl)piperidine inEtOH (30 ml), mercury oxide (800 mg) was added and the mixture wasrefluxed for 1 hour. The solvent was distilled off under reducedpressure to obtain 1-Boc-4-(dihydroquinazoline-2-aminomethyl)piperidine.The compound was identified by LC-MS.

M+1=345.2.

After dissolving the1-Boc-4-(dihydroquinazoline-2-aminomethyl)piperidine in methanol (10ml), a 4N hydrogen chloride/1,4-dioxane solution (16 ml) was added andthe mixture was stirred at 50° C. for 90 minutes. The solvent wasdistilled off under reduced pressure to obtain4-(dihydroquinazoline-2-aminomethyl)piperidine hydrochloride. Thecompound was identified by LC-MS.

Yield: 449 mg (89%), M+1=245.1.

Examples 4-1 to 4-5

Compound Nos. 4-1 to 4-5 were synthesized in the same manner as Example2-5, using the corresponding reactants. The results are shown in Table17.

Example 4-7 Synthesis of2,4-dichloro-6-[(4-{[(6-chloro(1,4-dihydroquinazolin-2-yl))amino]methyl}piperidyl)methyl]phenol

After dissolving Compound No. 2-193 (2.5 mg, 0.028 mmol) in THF (0.5mL), a 1N BH₃/THF solution (0.56 ml, 0.56 mmol) was added and themixture was stirred at 80° C. for 24 hours. A 5N NaOH aqueous solution(0.5 mL) was added to the obtained solution, and the mixture was stirredat 80° C. for 5 hours. The obtained solution was extracted with ethylacetate (2 mL×2 times), transferred to Sep-Pak-Dry (trade name ofVarian, sodium sulfate cartridge) for drying, and then transferred toSCX (Bond Elute SCX500MG). The SCX was washed with a CHCl₃/MeOH (1/1)mixed solution (5 mL) and then eluted with a 2N NH₃/MeOH solution (5mL). The eluate was concentrated and purified with a preparative HPLCsystem to obtain2,4-dichloro-6-[(4-{[(6-chloro(1,4-dihydroquinazolin-2-yl))amino]methyl}piperidyl)methyl]phenol.

Yield: 2.3 mg (19%), M+1=453.0.

Examples 4-6, 4-8 to 4-11

Compound Nos. 4-6 and 4-8 to 4-11 were synthesized in the same manner asExample 4-2, using the corresponding reactants. The results are shown inTable 17. TABLE 17 Compound Yield Yield No. 4- (mg) (%) MW M + 1 1 3.610 402.2 403.2 2 2.7 16 418.1 419.0 3 7.7 50 384.1 385.1 4 1.0 7 384.1385.1 5 6.6 61 362.2 363.2 6 2.6 25 502.1 503.1 7 2.3 19 452.1 453.0 81.4 3 432.2 433.1 9 6.3 12 436.1 437.1 10 2.1 4 432.2 433.1 11 2.8 6434.1 435.1

Synthesis of 2-[(4-piperidinylmethyl)amino]hydrothiopheno[3,2,d]pyrimidin-4-one derivatives Reference Example 5-1 Synthesis of3-{[(phenylcarbonylamino)thioxomethyl]amino}thiophene-2-carboxylic acidmethyl ester

A solution of benzoyl isothiocyanate (1038 mg, 6.36 mmol) in acetone (3mL) was added to absolution of 3-aminothiophene-2-carboxylic acid methylester (500 mg, 3.18 mmol) in acetone (3 mL). The mixture was stirred atroom temperature for 10 hours and then concentrated, and the residue waspurified by silica gel chromatography (Hex/EtOAc=10/1) to obtain3-{[(phenylcarbonylamino) thioxomethyl]amino}thiophene-2-carboxylic acidmethyl ester.

Yield: 866 mg (85%), M+1=321.0.

Reference Example 5-2 Synthesis of potassiumhydrothiopheno[3,2,d]pyrimidin-4-one-2-thiolate

A solution of3-{[(phenylcarbonylamino)thioxomethyl]amino}thiophene-2-carboxylic acidmethyl ester (866 mg, 2.7 mmol) in EtOH (3 mL) was added to a solutionof KOH (303 mg, 5.4 mmol) in EtOH (10 mL). The mixture was stirred for 3hours while heating to reflux, and the separated white precipitate wasfiltered out. It was then washed with EtOH (5 mL×2 times) and driedunder reduced pressure to obtain potassiumhydrothiopheno[3,2,d]pyrimidin-4-one-2-thiolate.

Yield: 476-mg (79%).

NMR (DMSO-d₆): δH 6.85(m, 1H), 7.22(m, 1H), 10.41(br, 1H)

Reference Example 5-3 Synthesis of2-methylthiohydrothiopheno[3,2,d]pyrimidin-4-one

MeI (133 μL, 2.14 mmol) was added to an aqueous solution (10 mL) ofpotassium hydrothiopheno[3,2,d]pyrimidin-4-one-2-thiolate (476 mg, 2.14mmol). The mixture was stirred at room temperature for 3 hours, and theseparated white precipitate was filtered out. It was then washed withwater (5 mL×2 times) and dried under reduced pressure to obtain2-methylthiohydrothiopheno[3,2,d]pyrimidin-4-one.

Yield: 337 mg (79%).

NMR (DMSO-d₆): δH 2.49(s, 1H), 7.26(d, J=5.4, 1H), 8.08(d, J=5.4, 1H)

Reference Example 5-4 Synthesis of2-[(1-Boc-4-piperidinylmethyl)amino]hydrothiopheno[3,2,d]pyrimidin-4-one

After adding 287 mg of 60% 3-chloroperbenzoic acid (1.0 mmol) to asolution of 200 mg (1.0 mmol) of2-methylthiohydrothiopheno[3,2,d]pyrimidin-4-one in chloroform (5 mL)while cooling on ice, the mixture was stirred at room temperature for 2hours. The obtained solution was concentrated, and then 235 mg (1.1mmol) of the compound 1-Boc-4-aminomethylpiperidine, 0.2 mL (1.5 mmol)of triethylamine and diglyme (diethyleneglycol dimethyl ether) (5 mL)were added. The obtained solution was stirred at 180° C. for 10 hours,and then water (10 mL) was added, and the mixture was extracted withethyl acetate (5 mL×2 times) and dried over magnesium sulfate. Afterfiltration, the filtrate was concentrated and the residue was purifiedby silica gel chromatography (Hex/EtOAc=1/1→0/1) to obtain2-[(1-Boc-4-piperidinylmethyl)amino]hydrothiopheno[3,2,d]pyrimidin-4-one.

Yield: 160 mg (44%).

LC/MS (LC/MSD): (M+H)+=365.1 (Found:) M=364.16 (calculated).

Reference Example 5-5 Synthesis of2-[(4-piperidinylmethyl)amino]hydrothiopheno [3,2,d]pyrimidin-4-one

The compound was synthesized in the same manner as Reference Example2-11.

Yield: 135 mg (90%), M+1=265.1.

Example 5-1

Compound No. 5-1 was synthesized by the same method as Example 2-5,using the compounds synthesized by Reference Examples 5-1 to 5-5. Theresults are shown in Table 18. TABLE 18 Compound Yield Yield No. 5- (mg)(%) MW M + 1 1 17.0 42 438.0 439.0

Synthesis of 5-methyl-2-[(4-piperidinylmethyl)amino]hydropyrrolo[3,2,d]pyrimidin-4-one derivatives Reference Example 6-1 Synthesis of5-methyl-2-[(4-piperidinylmethyl)amino]hydropyrrolo[3,2,d]pyrimidin-4-one

The title compound was obtained by synthesis in the same manner asReference Examples 5-1 to 5-5, using3-amino-1-methylpyrrolo-2-carboxylic acid ethyl ester as the startingmaterial.

Yield: 245 mg (92%), M+1=262.1 (Found:) M=261.1 (calculated).

Example 6-1

Compound No. 6-1 was synthesized by the same method as Example 2-5,using the compound synthesized by Reference Example 6-1. The results areshown in Table 19. TABLE 19 Compound Yield Yield No. 6- (mg) (%) MW M +1 1 4.0 11 436.3 436.1

Synthesis of2-[(4-piperidinylmethyl)amino]-1H,5H-benzo[f]1,3-diazepin-4-onederivatives Reference Example 7-1 Synthesis of4-{[({[2-(carbamoylmethyl)phenyl]amino}thioxomethyl)amino]methyl}piperidinecarboxylic acid tert-butyl ester

After dissolving 1-N-Boc-4-aminomethylpiperidine (869 mg, 4.06 mmol) inacetonitrile (10 mL), a solution of thiocarbonyldiimidazole (794 mg,4.46 mmol) and imidazole (82.9 mg, 1.22 mmol) in acetonitrile (15 mL)was added dropwise in an ice bath, and the mixture was stirred at roomtemperature for 4 hours. After then adding 2-(2-aminophenyl)acetamide(670 mg, 4.46 mmol) thereto, the mixture was stirred overnight at 60° C.The reaction mixture was concentrated under reduced pressure and theobtained residue was purified by silica gel column chromatography(methylene chloride/methanol=65:1→49:1) to obtain the title compound.

Yield: 1.41 g (85%), M+1=407.2 (found), M=406.2 (calculated).

Reference Example 7-2 Synthesis of 4-{[(4-oxo-1H,5H-benzo[f]1,3-diazepin-2-yl)amino]methyl}piperidine carboxylic acidtert-butyl ester

After dissolving4-{[({[2-(carbamoylmethyl)phenyl]amino}thioxomethyl)amino]methyl}piperidinecarboxylic acid tert-butyl ester (410 mg, 1.01 mmol) in tetrahydrofuran(15 mL), N,N′-dicyclohexylcarbodiimide (208 mg, 1.01 mmol) was added andthe mixture was stirred at room temperature for 6 hours. The filtrateobtained by filtering the insoluble portion was concentrated underreduced pressure, and the concentrate was suspended in a solution ofn-hexane:ethyl acetate=1:2 (3 mL). The insoluble portion was refiltered,and the residue obtained by concentrating the filtrate under reducedpressure was purified by silica gel column chromatography(n-hexane/ethyl acetate=2/3→1/2) to obtain the title compound. Yield:193 mg (51%).

¹³C-NMR (100 MHz, CDCl₃): δ=156.6, 155.0, 136.1, 129.6, 129.2, 126.6,126.2, 117.9, 79.7, 45.6, 36.7, 29.7, 28.5, 20.5

¹H-NMR (400 MHz, CDCl₃): δ=7.38(1H, d, J=7.3 Hz), 7.18-7.32(3H, m),7.14(1H, s), 5.43(1H, s), 4.07(2H, s), 3.71(2H, s), 3.06(1H, s),2.65(2H, m), 1.61(3H, m), 1.48(9H, s), 1.05(2H, m)

Reference Example 7-3 Synthesis of2-[(4-piperidinylmethyl)amino]-1H,5H-benzo[f]1,3-diazepin-4-one

The title compound was synthesized in the same manner as ReferenceExample 2-11, using 4-{[(4-oxo-1H,5H-benzo[f]1,3-diazepin-2-yl)amino]methyl}piperidine carboxylic acidtert-butyl ester as the starting material.

Yield: 218 mg (quantitative, M+1=273.1 (Found:) M=272.2 (calculated).

Example 7-1

Compound Nos. 7-16 and 7-504 were synthesized by the same method asExample 2-5, using reactants for the compounds synthesized by ReferenceExamples 7-1 to 7-3. The results are shown in Table 20. TABLE 20Compound Yield Yield No. 7- (mg) (%) MW M + 1 16 4.0 10 447.4 447.1 5046.0 16 430.9 431.1

Synthesis of [2-[(4-piperidylmethyl)amino]hydroquinazolin-4-onederivatives Example 8-16 Synthesis of2-[({1-[(3,5-dichloro-2-hydroxy-phenyl)methyl]-4-piperidyl}methyl)amino]hydroquinazoline-4-thione

After placing 5.7 mg (0.0132 mol) of Compound No. 2-16 in a 15 mLround-bottomed flask equipped with a magnetic stirrer, it was dissolvedin 1 g of phosphorous oxychloride and the solution was stirred for onehour at a bath temperature of 120° C. The phosphorus oxychloride wasdistilled off by concentration under reduced pressure, and then 84.2 mg(1.106 mmol) of thiourea and 4 mL of 1,4-dioxane were added and themixture was refluxed for 1 hour. After distilling off the solvent, theresidue was suspended in methanol, solid phase extraction was performedwith an SCX column, and the eluate obtained by elution with a 2 Mammonia/methanol solution was concentrated and purified by preparativeHPLC. The fraction containing the target substance was concentrated toobtain2-[({1-[(3,5-dichloro-2-hydroxy-phenyl)methyl]-4-piperidyl}methyl)amino]hydroquinazoline-4-thioneas a colorless powder. The results are shown in Table 21. TABLE 21Compound Yield Yield No. 8- (mg) (%) MW M + 1 16 0.6 10 449.4 449.1

Example 9

Measurement of Inhibiting Power of Test Compounds AgainstEotaxin-Induced Intracellular Calcium Concentration Increase inCCR3-Expressing Cells

K562 cells stably expressing CCR3 receptor were used in the followingmethod for measurement of the inhibiting power of compounds of theinvention against intracellular calcium concentration increase.

The CCR3-expressing K562 cells were suspended in HBSS solution (Hanks'Balanced Salt Solution, Gibco BRL) containing 10 mM HEPES(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid], Gibco BRL),and then 1 mM Fura-2 acetoxymethyl ester (product of Dojin Kagaku) wasadded to a final concentration of 1 μM and the mixture was incubated at37° C. for 30 minutes. After rinsing the cells, they were addedsimultaneously with the test compound into a 96-well white plate(Falcon), the agonist was added after 5 minutes, the mixture was excitedat 340 nm and 380 nm, and the 340/380 ratio was monitored to measure theintracellular calcium concentration. Human eotaxin (product of GenzymeTechne) (0.5 μg/ml) was used as an agonist. The inhibiting power of thetest compound was determined by measuring the intracellular calciumconcentration upon treatment of the CCR3-expressing K562 cells with thetest compound 5 minutes before eotaxin stimulation, and calculating thesuppression by the following formula.Suppression (%)={1−(A−B)/(C−B)}×100(A: Intracellular calcium concentration upon stimulation with eotaxinafter treatment with test compound, B: Intracellular calciumconcentration without stimulation, C: Intracellular calciumconcentration upon stimulation with eotaxin without treatment with testcompound)

The inhibiting power of piperidine derivatives of the invention wasmeasured, and for example, the compounds having the Compound Nos. listedbelow demonstrated inhibiting power of 20-50%, 50-80% or 80% or greater,at 10 μM or 2 μM concentrations of the compounds.

The following compounds exhibited 20-50% inhibition at 10 μMconcentration:

Compound No. 1—: 1-7, 1-9, 2-5, 2-6, 2-8, 2-12, 2-13, 2-15, 2-16, 2-18,2-21, 2-22, 2-24, 2-29, 2-31, 2-35, 2-43, 2-45, 2-48, 2-56, 2-70, 2-71,2-77, 2-85, 2-96, 2-100 to 2-103, 2-107, 2-108, 2-116, 2-128, 2-129,2-136, 2-141, 2-146, 2-147, 2-176 to 2-180, 3-8, 3-55, 3-56, 3-58, 5-37,5-98, 5-104, 5-113, 5-118, 5-122, 5-125, 5-127, 5-141, 6-4 to 6-6, 6-8.

The following compounds exhibited 50-80%-inhibition at 10 μMconcentration:

Compound No. 1—: 1-3 to 1-6, 1-10, 1-11, 2-2 to 2-4, 2-23, 2-30, 2-33,2-34, 2-39, 2-41, 2-42, 2-47, 2-49, 2-51, 2-54, 2-57, 2-60, 2-61, 2-64to 2-66, 2-73, 2-80 to 2-82, 2-84, 2-89 to 2-91, 2-95, 2-106, 2-109,2-112, 2-113, 2-115, 2-120, 2-122, 2-123, 2-127, 2-130, 2-133, 2-134,2-137, 2-138, 2-142, 2-142, 2-170, 2-173 to 2-175, 3-7, 3-9, 4-29, 5-20,5-21, 5-30, 5-36, 5-39, 5-40, 5-42 to 5-45, 5-49, 5-65, 5-72, 5-96,5-97, 5-99, 5-101 to 5-103, 5-108, 5-109, 5-111, 5-115, 5-117, 5-119,5-121, 5-128 to 5-130, 5-134, 5-135, 5-137 to 5-139, 5-142, 5-147,5-148, 5-154 to 5-158, 5-167, 5-168, 5-174, 5-175, 5-180, 5-181, 5-183

Compound No. 2—: 2 to 4

The following compounds exhibited ≧80% inhibition at 10 μMconcentration:

Compound No. 1—: 1-1, 1-8, 2-1, 2-14, 2-36 to 2-38, 2-40, 2-50, 2-52,2-72, 2-75, 2-98, 2-117 to 2-119, 2-121, 2-124 to 2-126, 2-131, 2-149 to2-151, 2-153, 2-154, 3-2, 3-13, 3-15, 3-17, 3-18, 3-21 to 3-23, 3-25,3-26, 3-28 to 3-30, 3-32 to 3-38, 3-42 to 3-52, 3-59, 3-61, 3-62, 5-22to 5-29, 5-31 to 5-35, 5-38, 5-41, 5-46 to 5-48, 5-50 to 5-64, 5-66 to5-71, 5-88 to 5-93, 5-95, 5-107, 5-110, 5-114, 5-116, 5-120, 5-123,5-124, 5-126, 5-131 to 5-133, 5-136, 5-140, 5-143 to 5-146, 5-149 to5-153, 5-159 to 5-166, 5-169 to 5-173, 5-176 to 5-179, 5-182, 6-7, 6-9,6-11 to 6-13, 6-15

Compound No. 2—: 1

Compound No. 4—: 1

The following compounds exhibited 20-50% inhibition at 2 μMconcentration:

Compound No. 1—: 2-156 to 2-159, 2-163, 2-164, 3-14, 3-24, 3-27, 3-40,4-1, 4-3, 4-4, 4-6, 5-15, 5-16, 5-74, 5-75, 5-77, 5-79, 5-82, 5-84, 5-85

Compound No. 2—: 5, 7, 8, 13, 22, 24, 200, 232, 243, 245, 247,

The following compounds exhibited 50-80% inhibition at 2 μMconcentration:

Compound No. 1—: 2-166, 2-168, 2-169, 3-4, 3-11, 3-16, 3-31, 4-12, 4-15to 4-17, 5-7, 5-8, 5-14, 5-19, 5-73, 5-76, 5-78, 5-80, 5-81, 5-83, 5-86,5-188

Compound No. 2—: 6, 10, 14, 16, 17, 20, 21, 23, 29, 196, 205, 221, 223,224, 234, 237, 244, 495

Compound No. 4—: 5

Compound No. 7—: 504

The following compounds exhibited ≧80% inhibition at 2 μM concentration:

Compound No. 1—: 2-160, 2-162, 2-165, 2-167, 3-1, 3-3, 3-5, 3-6, 4-10,4-11, 4-13, 4-14, 4-18 to 4-21, 5-1 to 5-6, 5-9 to 5-13, 5-17, 5-18,5-184 to 5-187, 5-189, 5-190

Compound No. 2—: 11, 12, 15, 18, 19, 26 to 28, 30, 186 to 195, 197 to199, 201 to 204, 206 to 220, 225 to 231, 235, 236, 238 to 242, 246, 248to 250, 499, 511, 513, 565

Compound No. 3—: 1-10, 208, 220, 223, 235, 238, 368, 504, 505, 511, 523,525, 526, 527, 555, 577

Compound No. 4—: 2 to 4, 6 to 11

Compound No. 6—: 1

Compound No. 7—: 16, 504

Compound No. 8—: 16

Example 10

Measurement of Inhibiting Power Against Eotaxin Binding toCCR3-Expressing Cells

Human CCR3-expressing L1.2 cells were suspended in assay buffer[RPMI1640 (phenol red free), 25 mM HEPES (pH 7.4), 0.1% NaN₃, 0.1%gelatin, 0.08% CHAPS] to prepare a 5×10⁵/mL whole cell suspension. Asolution of the test compound diluted with assay buffer was prepared asthe test compound solution. A solution of [¹²⁵I]-labeled human eotaxin(Amersham) diluted with assay buffer to 1 μCi/mL was prepared as thelabeled ligand solution. After dispensing 25 μL of the test compoundsolution, 25 μL of the labeled ligand solution and 50 μL of the wholecell suspension in that order into each well of a 96-well microplate(Falcon) covered with 0.5% BSA and stirring (100 μL of reactionsolution), incubation was performed at 25° C. for 90 minutes.

After completion of the reaction, a 96-well filter plate (Millipore)containing filters immersed in 0.5% polyethyleneimine solution was usedfor filter filtration of the reaction mixture, with washing of thefilters four times with 150 μL of cold washing buffer (assay buffer+0.5M NaCl) (filtering was performed after adding 150 μL of cold washingbuffer). The filters were blow-dried, and then 25 μL of liquidscintillator (MicroScient-O, Packard) was added to each well and theradioactivity incorporated in each membrane fraction on the filter wasmeasured by a Top Count (Packard).

The count upon addition of 100 ng of unlabeled human eotaxin instead ofthe test compound was subtracted as the non-specific adsorption, tocalculate the inhibiting power of the test compound against binding ofhuman eotaxin to the CCR3 expressing cells, with 100% as the count withno addition of the test compound.Inhibiting power (%)={1−(A−B)/(C−B)}×100(A: Count upon addition of test compound, B: Count upon addition of 100ng of unlabeled human eotaxin, C: Count upon addition of [¹²⁵I]-labeledhuman eotaxin alone)

Example 11

Measurement of Inhibiting Power of Test Compounds on Eotaxin-InducedCell Migration of CCR3-Expressing Cells

L1.2 cells stably expressing CCR3 receptor were used to measure theinhibiting power of compounds of the invention against cell migration,by the following method.

The test compound was suspended in 0.5% BSA-containing RPMI1640 (GibcoBRL) solution and human eotaxin (product of Genzyme Techne) (20 ng/mL)was added as an agonist, and then the mixture was placed in the lowercompartment of a 96-well chemotaxis chamber (Neuro Probe, Inc.) and aspecial chemotaxis chamber filter was inserted in the upper compartment.After adding the same test compound and CCR3-expressing L1.2 cells tothe upper compartment, incubation was performed at 37° C. for 2 hours.

Upon completion of the reaction, the special filter was stained with ascreening blood staining solution (Diff-Quick, Kokusai Shiyaku Co.,Ltd.), the absorbance at 550 nm was measured, and the suppression (%)was calculated according to the following formula.Suppression (%)={1−(A−B)/(C−B)}×100(A: Cell migration upon eotaxin stimulation of CCR3-expressing L1.2cells treated with test compound, B: cell migration without stimulation,C: cell migration upon eotaxin stimulation without treatment with testcompound)

Upon measurement of several of the compounds of the invention as testcompounds in Examples 10 and 11, the inhibiting power was found to beessentially the same as in Example 9.

INDUSTRIAL APPLICABILITY

The compounds represented by formula (I) of the present inventionexhibit activity which inhibits binding of CCR3 ligands such as eotaxinsto their target cells and activity of inhibiting the physiologicaleffects of binding of CCR3 ligands such as eotaxins to their targetcells, and can therefore be utilized as CCR3 antagonists. LENGTHY TABLEThe patent application contains a lengthy table section. A copy of thetable is available in electronic form from the USPTO web site(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20070032525A1)An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A compound represented by the following formula (I):

[wherein R¹ represents phenyl, C₃-C₈ cycloalkyl or an aromaticheterocyclic group (having 1-3 atoms selected from the group consistingof oxygen, sulfur and nitrogen as hetero atoms), the phenyl or aromaticheterocyclic group of R¹ may optionally fuse with a benzene ring oraromatic heterocyclic group (having 1-3 atoms selected from the groupconsisting of oxygen, sulfur and nitrogen as hetero atoms) to form afused ring, the phenyl, C₃-C₈ cycloalkyl or aromatic heterocyclic group,or fused ring, in R¹ may be unsubstituted, or substituted with one ormore substituents selected from the group consisting of halogens,hydroxy, cyano, nitro, carboxyl, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₂-C₆alkenyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₃-C₅ alkylene, C₂-C₄alkyleneoxy, C₁-C₃ alkylenedioxy, phenyl, phenoxy, phenylthio, benzyl,benzyloxy, benzoylamino, formyl, C₂-C₇ alkanoyl, C₂-C₇ alkoxycarbonyl,C₂-C₇ alkanoyloxy, C₂-C₇ alkanoylamino, C₁-C₆ alkylsulfonyl, C₃-C₈(alkoxycarbonyl)methyl, amino, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, carbamoyl, C₂-C₇ N-alkylcarbamoyl, C₄-C₉N-cycloalkylcarbamoyl, N-phenylcarbamoyl, piperidylcarbonyl,morpholinylcarbonyl, pyrrolidinylcarbonyl, piperazinylcarbonyl,N-methoxycarbamoyl, (formyl)amino and ureido, and the substituent of thephenyl, C₃-C₈ cycloalkyl or aromatic heterocyclic group, or fused ring,of R¹ may be unsubstituted, or substituted with one or more substituentsselected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, phenyl, C₃-C₅ alkylene, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl,C₁-C₆ alkoxy, C₁-C₆ alkylthio, amino, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, pyrrolidinyl, piperidyl, C₃-C₇ lactam, carbamoyl, C₂-C₇N-alkylcarbamoyl, C₂-C₇ alkoxycarbonyl, carboxyl, hydroxy, benzoyl,cyano, trifluoromethyl, halogen and tert-butoxycarbonylamino, providedthat when R¹ is C₃-C₈ cycloalkyl, the substituent does not includeamino, mono(C₁-C₆ alkyl)amino or di(C₁-C₆ alkyl)amino; p represents aninteger of 1-6; R² and R³ may be the same or different and eachindependently represents hydrogen, C₁-C₆ alkyl or phenyl, where theC₁-C₆ alkyl or phenyl group of R² and R³ may be unsubstituted, orsubstituted with one or more substituents selected from the groupconsisting of halogens, hydroxy, C₁-C₆ alkyl, C₂-C₇ alkoxycarbonyl,amino, carbamoyl, carboxyl, cyano and C₁-C₆ alkoxy; X represents —CO—,—SO₂—, —CH₂—, —CS— or a single bond; q represents 0 or 1; r represents 0or 1; Y represents —(R⁴)C═C(R⁵)—, —S— or —NR⁸—; R⁴, R⁵, R⁶ and R⁷ may bethe same or different, and each independently represents hydrogen, ahalogen, hydroxy, cyano, nitro, carboxyl, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₂-C₆ alkenyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₃-C₅ alkylene, C₂-C₄alkyleneoxy, C₁-C₃ alkylenedioxy, phenyl, phenoxy, phenylthio,phenylsulfonyl, benzyl, benzyloxy, benzoylamino, formyl, C₂-C₇ alkanoyl,C₂-C₇ alkoxycarbonyl, C₂-C₇ alkanoyloxy, C₂-C₇ alkanoylamino, C₄-C₁₀cycloalkanoylamino, C₃-C₇ alkenoylamino, C₁-C₆ alkylsulfonyl, C₁-C₆alkylsulfonylamino, C₃-C₈ (alkoxycarbonyl)methyl, amino, mono(C₁-C₆alkyl)amino, di(C₁-C₆ alkyl)amino, carbamoyl, C₂-C₇ N-alkylcarbamoyl,C₄-C₉ N-cycloalkylcarbamoyl, N-phenylcarbamoyl, N—(C₇-C₁₂phenylalkyl)carbamoyl, piperidylcarbonyl, morpholinylcarbonyl,pyrrolidinylcarbonyl, piperazinylcarbonyl, N-methoxycarbamoyl,sulfamoyl, C₁-C₆ N-alkylsulfamoyl, (formyl)amino, (thioformyl)amino,ureido or thioureido, where the aforementioned groups of R⁴, R⁵, R⁶ andR⁷ each may be independently unsubstituted, or substituted with one ormore substituents selected from the group consisting of C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, phenyl, C₃-C₅ alkylene, C₃-C₈ cycloalkyl,C₃-C₈ cycloalkenyl, C₁-C₆ alkoxy, (C₁-C₆ alkoxy) (C₁-C₆ alkoxy),phenyl(C₁-C₆ alkoxy), C₁-C₆ alkylthio, amino, mono(C₁-C₆ alkyl)amino,di(C₁-C₆ alkyl) amino, pyrrolidinyl, piperidyl, (C₂-C₇alkanoyl)piperidyl, C₃-C₇ lactam, carbamoyl, C₂-C₇ N-alkylcarbamoyl,C₄-C₉ N-cycloalkylcarbamoyl, N-phenylcarbamoyl, N—(C₇-C₁₂phenylalkyl)carbamoyl, C₂-C₇ alkanoylamino, C₂-C₇ alkoxycarbonyl,carboxyl, hydroxy, benzoyl, cyano, trifluoromethyl, halogens,tert-butoxycarbonylamino, C₁-C₆ alkylsulfonyl and heterocycles oraromatic heterocycles (where a heterocycle or aromatic heterocycle has1-3 atoms selected from the group consisting of oxygen, sulfur andnitrogen as hetero atoms, and may be substituted with C₁-C₆ alkyl); andR⁸ represents hydrogen or C₁-C₆ alkyl, where the C₁-C₆ alkyl group of R⁸may be unsubstituted, or substituted with one or more substituentsselected from the group consisting of halogens, hydroxy, cyano, nitro,carboxyl, carbamoyl, mercapto, guanidino, C₃-C₈ cycloalkyl, C₁-C₆alkoxy, C₁-C₆ alkylthio, phenyl (where phenyl may be substituted, orsubstituted with one or more substituents selected from the groupconsisting of halogens, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy andbenzyloxy), phenoxy, benzyloxy, benzyloxycarbonyl, C₂-C₇ alkanoyl, C₂-C₇alkoxycarbonyl, C₂-C₇ alkanoyloxy, C₂-C₇ alkanoylamino, C₂-C₇N-alkylcarbamoyl, C₂-C₆ alkylsulfonyl, amino, mono(C₁-C₆ alkyl)amino,di(C₁-C₆ alkyl)amino and ureido], a pharmaceutically acceptable acidadduct thereof, or a pharmaceutically acceptable C₁-C₆ alkyl adductthereof.
 2. A compound according to claim 1, a pharmaceuticallyacceptable acid adduct thereof, or a pharmaceutically acceptable C₁-C₆alkyl adduct thereof, wherein X in formula (I) is —SO₂—.
 3. A compoundaccording to claim 1, a pharmaceutically acceptable acid adduct thereof,or a pharmaceutically acceptable C₁-C₆ alkyl adduct thereof, wherein Xin formula (I) is —CO—.
 4. A compound according to claim 1, apharmaceutically acceptable acid adduct thereof, or a pharmaceuticallyacceptable C₁-C₆ alkyl adduct thereof, wherein X in formula (I) is—CH₂—.
 5. A compound according to claim 1, a pharmaceutically acceptableacid adduct thereof, or a pharmaceutically acceptable C₁-C₆ alkyl adductthereof, wherein X in formula (I) is —CS—.
 6. A compound according toclaim 1, a pharmaceutically acceptable acid adduct thereof, or apharmaceutically acceptable C₁-C₆ alkyl adduct thereof, wherein X informula (I) is a single bond.
 7. A compound according to any one ofclaims 1 to 6, a pharmaceutically acceptable acid adduct thereof, or apharmaceutically acceptable C₁-C₆ alkyl adduct thereof, wherein Y informula (I) is —(R⁴)C═C(R⁵)—.
 8. A compound according to any one ofclaims 1 to 6, a pharmaceutically acceptable acid adduct thereof, or apharmaceutically acceptable C₁-C₆ alkyl adduct thereof, wherein Y informula (I) is —S—.
 9. A compound according to any one of claims 1 to 6,a pharmaceutically acceptable acid adduct thereof, or a pharmaceuticallyacceptable C₁-C₆ alkyl adduct thereof, wherein Y in formula (I) is—NR⁸—.
 10. A compound according to any one of claims 1 to 9, apharmaceutically acceptable acid adduct thereof, or a pharmaceuticallyacceptable C₁-C₆ alkyl adduct thereof, wherein R¹ in formula (I) issubstituted or unsubstituted phenyl.
 11. A compound according to any oneof claims 1 to 10, a pharmaceutically acceptable acid adduct thereof, ora pharmaceutically acceptable C₁-C₆ alkyl adduct thereof, wherein R² informula (I) is hydrogen.
 12. A compound according to any one of claims 1to 11, a pharmaceutically acceptable acid adduct thereof, or apharmaceutically acceptable C₁-C₆ alkyl adduct thereof, wherein R³ informula (I) is hydrogen.
 13. A compound according to any one of claims 1to 12, a pharmaceutically acceptable acid adduct thereof, or apharmaceutically acceptable C₁-C₆ alkyl adduct thereof, wherein q=0 andr=0 in formula (I).
 14. A compound according to any one of claims 1 to12, a pharmaceutically acceptable acid adduct thereof, or apharmaceutically acceptable C₁-C₆ alkyl adduct thereof, wherein q=1 andr=0 in formula (I).
 15. A compound according to any one of claims 1 to12, a pharmaceutically acceptable acid adduct thereof, or apharmaceutically acceptable C₁-C₆ alkyl adduct thereof, wherein q=0 andr=1 in formula (I).
 16. A compound according to any one of claims 1 to15, a pharmaceutically acceptable acid adduct thereof, or apharmaceutically acceptable C₁-C₆ alkyl adduct thereof, wherein p=1 informula (I).
 17. A compound according to claim 2, a pharmaceuticallyacceptable acid adduct thereof, or a pharmaceutically acceptable C₁-C₆alkyl adduct thereof, wherein Y is —(R⁴)C═C(R⁵)—, R¹ is substituted orunsubstituted phenyl, R² is hydrogen, R³ is hydrogen, q=0, r=0 and p=1in formula (I).
 18. A compound according to claim 3, a pharmaceuticallyacceptable acid adduct thereof, or a pharmaceutically acceptable C₁-C₆alkyl adduct thereof, wherein Y is —(R⁴) C═C(R⁵)—, R¹ is substituted orunsubstituted phenyl, R² is hydrogen, R³ is hydrogen, q=0, r=0 and p=1in formula (I).
 19. A compound according to claim 4, a pharmaceuticallyacceptable acid adduct thereof, or a pharmaceutically acceptable C₁-C₆alkyl adduct thereof, wherein Y is —(R⁴)C═C(R⁵)—, R¹ is substituted orunsubstituted phenyl, R² is hydrogen, R³ is hydrogen, q=0, r=0 and p=1in formula (I).
 20. A compound according to claim 6, a pharmaceuticallyacceptable acid adduct thereof, or a pharmaceutically acceptable C₁-C₆alkyl adduct thereof, wherein Y is —(R⁴) C═C(R⁵)—, R¹ is substituted orunsubstituted phenyl, R² is hydrogen, R³ is hydrogen, q=0, r=0 and p=1in formula (I)
 21. A compound according to any one of claims 17 to 20, apharmaceutically acceptable acid adduct thereof, or a pharmaceuticallyacceptable C₁-C₆ alkyl adduct thereof, wherein R⁴ and R⁵ in formula (I)may be the same or different and each is independently hydrogen, ahalogen, hydroxy, cyano, nitro, carboxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₂-C₇ alkoxycarbonyl, C₂-C₇ alkanoylamino, C₁-C₆ alkylsulfonyl, amino,carbamoyl, C₂-C₇ N-alkylcarbamoyl, sulfamoyl or C₁-C₆ N-alkylsulfamoyl.22. A compound according to any one of claims 17 to 20, apharmaceutically acceptable acid adduct thereof, or a pharmaceuticallyacceptable C₁-C₆ alkyl adduct thereof, wherein R⁴ and R⁵ in formula (I)may be the same or different and each is independently a halogen,hydroxy, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₇ alkoxycarbonyl,C₁-C₆ alkylsulfonyl or C₁-C₆ N-alkylsulfamoyl.
 23. A compound accordingto any one of claims 17 to 22, a pharmaceutically acceptable acid adductthereof, or a pharmaceutically acceptable C₁-C₆ alkyl adduct thereof,wherein each R¹ in formula (I) above may be the same or different and isindependently hydrogen, a halogen, hydroxy, cyano, nitro, C₁-C₆ alkyl orC₁-C₆ alkoxy.
 24. A pharmaceutical composition with CCR3 antagonism,which comprises as an effective ingredient thereof a compoundrepresented by formula (I) above according to any one of claims 1 to 23,a pharmaceutically acceptable acid adduct thereof or a pharmaceuticallyacceptable C₁-C₆ alkyl adduct thereof.
 25. A prophylactic and/ortherapeutic composition for any disease associated with CCR3, whichcomprises as an effective ingredient thereof a compound represented byformula (I) above according to any one of claims 1 to 23, apharmaceutically acceptable acid adduct thereof or a pharmaceuticallyacceptable C₁-C₆ alkyl adduct thereof.
 26. A prophylactic and/ortherapeutic composition according to claim 25, wherein said disease isan allergic condition.
 27. A prophylactic and/or therapeutic compositionaccording to claim 26, wherein said allergic condition is bronchialasthma, allergic rhinitis, atopic dermatitis, urticaria, contactdermatitis or allergic conjunctivitis.
 28. A prophylactic and/ortherapeutic composition according to claim 25, wherein said disease isinflammatory bowel disease.
 29. A prophylactic and/or therapeuticcomposition according to claim 25, wherein said disease is AIDS(Acquired Immune Deficiency Syndrome).
 30. A prophylactic and/ortherapeutic composition according to claim 25, wherein said disease iseosinophilia, eosinophilic gastroenteritis, eosinophilic enteropathy,eosinophilic fasciitis, eosinophilic granuloma, eosinophilic pustularfolliculitis, eosinophilic pneumonia or eosinophilic leukemia.